Periodontology 2000, Vol.

43, 2007, 1440

Printed in Singapore. All rights reserved

 2007 The Authors.

Journal compilation  2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

The role of T cells in periodontal

disease: homeostasis and
autoimmunity
E R I C A G E M M E L L , K A Z U H I S A Y A M A Z A K I & G R E G O R Y J. S E Y M O U R

It is now over 30 years since the seminal paper of

Ivanyi and Lehner (106) suggested a fundamental
role for T cells in periodontal disease. It is well
established that the development of gingivitis is
identical to the development of a delayed-type
hypersensitivity reaction and that the so-called stable lesion is essentially a T-cell-mediated response.
On the other hand, numerous studies have shown
that periodontitis is predominantly a B-cell response
with T cells having an immunoregulatory role.
Recently however it has been shown that, albeit in
mice, the periodontopathic organism Porphyromonas gingivalis down-regulates well over a
thousand genes in CD4-positive T cells while
up-regulating only about 30 genes. The role of
autoimmunity has also been revived with the
demonstration of both anti-collagen and anti-heatshock protein 60-reactive T cells in the gingival tissues. In addition, the so-called T regulatory or Treg
cells have been demonstrated in periodontal tissues.
These cells are thought to have a central role in the
control of autoimmunity. The question therefore
arises as to the role of T cells in periodontal disease.
This article will explore the concept that because P.
gingivalis is turning off T-cell genes it may be the
mechanism that enables a balance or stability to be
reached between the plaque biofilm and the host, i.e.
the role of T cells may be homeostatic rather than
defensive or destructive.
With respect to autoimmunity in periodontal disease the article will put forward the concept that this
is an important and normal component of chronic
inflammation. A possible scenario in this context
could be that because chronic inflammation is
defined as the simultaneous presence of destruction
and repair, as the tissue is destroyed, i.e. the collagen
is broken down by the various proteases, it must then

14

be removed and the amino acids must be made

available for re-use by the fibroblasts. The production
of anti-collagen antibodies could then opsonize the
broken down collagen fragments and enhance their
phagocytosis by fibroblasts, hence facilitating the
re-cycling process. Such a scenario would suggest
that the role of autoimmunity and therefore the
controlling mechanisms are an essential part of
homeostasis. Similarly, anti-heat-shock protein
reactions in chronic inflammation could be the
means of removing damaged or destroyed cells locally and again the role of T cells is homeostasis.

Introduction
It is well established that periodontal disease results
from the interaction of the hosts defense mechanisms with microorganisms in the dental plaque
biofilm. Since the 1990s, biofilms containing complexes including P. gingivalis, Fusobacterium nucleatum, Tannerella forsythia, and Treponema denticola
have been related to clinical measures of periodontal
disease, particularly pocket depth and bleeding on
probing (215). Notwithstanding these observations, it
has also been shown that there is a high degree of
volatility with respect to the numbers of these
organisms over time, such that it would appear that
they are more widespread in the community than
previously thought (42). Indeed, it is now recognized
that many people carry the organisms without
manifesting disease progression (42). In this context,
it is clear that most people are in balance with their
biofilm for most of the time and it is only when this
balance is disturbed that disease results. Such disturbances may involve changes in the relative
amounts of the respective cytokines or may involve

The role of T cells in periodontal disease

Fig. 1. Diagrammatic representation of the cytokine balance in periodontal disease. Moving the fulcrum to the
right even though there is no change in the relative
amounts of cytokines, favors the formation of a progressive lesion (A). Moving the fulcrum to the left again with
no change in the relative amounts of cytokines this time
favors the development of a stable lesion (B).

changes in the controlling cytokines without changes

in their respective amounts. These changes would be
akin to moving the fulcrum either to the left or right
as shown in Fig. 1. Such shifts could occur as a result
of environmental influences leading to an opportunistic increase in the numbers of organisms, a
depression of the hosts defense mechanisms or
indeed both. The innate susceptibility of the host
therefore reflects the interplay between the bacteria,
the hosts immune system, and environmental factors (41, 199).

T cells in periodontal disease

In 1965, Brandtzaeg and Kraus (26) demonstrated the
presence of immunoglobulin-producing plasma cells
in the gingival tissues of patients with periodontal
disease. This was the first direct evidence that adaptive immune mechanisms play a role in the pathogenesis of periodontal inflammation. It was not until
1970, however, that Ivanyi and Lehner (106) using

peripheral blood lymphocyte transformation assays

highlighted a role for cell-mediated immunity in
periodontal disease. Since then, immunohistological
studies have supported the concept that the response
to plaque bacteria is immunological in nature. An
experimental gingivitis study established that a
T-cell/macrophage lesion identical to a delayed
hypersensitivity reaction (178) occurs within 48 days
of plaque accumulation (204) and that this was synonymous with the early lesion of Page and Schroeder
(171) and with the putative stable lesion (200). The
expression of human leukocyte antigen DR and DQ
by the infiltrating T cells further suggested that these
cells are activated but the lack of CD25 expression
would indicate that they are not proliferating locally
within the tissues (204). In contrast, other early
studies demonstrated that the periodontitis lesion
involved predominantly B cells and plasma cells (128,
137, 181, 198, 202, 204) as well as a decrease in the
CD4 : CD8 ratio (39, 170, 220, 234).
The study by Ivanyi and Lehner (106) was the first
to report possible suppression of cell-mediated
immunity in advanced periodontitis subjects. The
induction of lymphocyte suppression by a number
of periodontopathic bacteria including P. gingivalis,
Actinobacillus actinomycetemcomitans, Treponema
denticola, Capnocytophaga ochracea, and F. nucleatum (71, 205207, 218) was then demonstrated. In
addition, T cells extracted from periodontal diseased
tissues were reported to have a reduced ability
to respond in an autologous mixed lymphocyte
reaction (39) supporting the suggestion of a suppression of cell-mediated responses in periodontitis.
Seymour et al. (203) demonstrated a lack of interleukin-2 (IL-2) production by unstimulated T cells
extracted from adult periodontitis patients and
suggested this to be a reason for the failure of these
cells to undergo spontaneous proliferation (38). In
support of this study, a reduced production of IL-2
and/or IL-2 receptor (IL-2R) expression by T cells in
patients with a reduced autologous mixed lymphocyte reaction has been shown (116). Furthermore,
the autologous mixed lymphocyte reaction has been
reported to return to normal following periodontal
therapy (222), supporting the concept that the
suppressive effect of plaque bacteria may be
fundamental in the conversion of a stable lesion to a
progressive lesion.
In recent years, herpesviruses have been associated
with destructive periodontal disease and in this
context it is well established that these and other
enveloped viruses induce a cellular immune
response, and an increase in CD8 T cells. In addition,

15

Gemmell et al.

EpsteinBarr virus promotes the proliferation of B

cells and it has been postulated that this response to
the periodontal presence of viruses could explain the
observed immunohistological changes and predominance of B cells in the progressive lesion (reviewed in
Ref. 213).
The reduced functional capacity of peripheral
blood mononuclear cells from periodontitis patients
with respect to their spontaneous proliferative
response compared with the response of cells from
healthy subjects has recently been revisited in a study
by Emingil et al. (60). However, because of the
complex etiology of periodontal disease, answers to
why periodontopathic bacteria induce their effects
have not yet been explained adequately. It is nevertheless possible to speculate that the role of T cells in
the stable lesion is one of homeostasis, i.e. of maintaining the balance between the host and the biofilm,
and it is when the balance shifts in favor of the
suppressive effect of the bacteria that disease progression occurs.
T cells are involved in nearly all immunoregulatory interactions both in vivo and in vitro (184) and
a delicate balance between effector and regulatory
subsets is required for immune homeostasis (183).
The production of appropriate cytokines in response to infection is necessary for the development of protective immunity (76). T helper type 1
(Th1) cells increase the ability of macrophages to
kill intracellular and extracellular pathogens and
also mediate delayed-type hypersensitivity reactions
(186).
Furthermore, there is evidence that T cells are
involved in the recruitment and activation of neutrophils at the site of infection (31, 46). Neutrophil
activation has been shown to require direct contact
with T cells and is independent of cytokine release
(262). Therefore in the stable lesion, activation of
neutrophils may be crucial in keeping the infection
under control. It has been suggested that a strong
innate immune response in the gingival tissues
leads to the production of IL-12, which in turn
leads to a Th1 response (76). The presence of natural killer cells in gingival tissues has also been
demonstrated (255) and may be significant in the
establishment of a Th1 response. The production of
interferon-c then enhances the phagocytic activity
of both neutrophils and macrophages and hence
containment of the infection.
It is also well established that the herpesviruses
promote the expression of Th1 cytokines, such that
containment of any viral influence would also favor a
Th1 response (reviewed in Ref. 213).

16

In contrast, the B-cell nature of the progressive

lesion (197) suggests either an increase in the
production of Th2 cytokines or a decline in the
production of Th1 cytokines. In other words, it
suggests a shift in the balance towards Th2. Gramnegative bacteria associated with disease progression have long been cited as being polyclonal B-cell
activators (reviewed in Refs 201 and 238), as has
EpsteinBarr virus (213). Therefore, as a result of
environmental factors causing growth of the plaque
biofilm, and hence an increase in the suppressive
effect of the bacteria, the biofilm may circumvent
the protective function of neutrophils and, concomitant with an increase in bacteria-derived
polyclonal B-cell activators, this may in turn lead to
the activation of B cells and their migration into
the lesion (72). Further proliferation of these B cells
could be induced by a local EpsteinBarr virus
infection (213).

Cytokine profiles in periodontal

disease
Studies over the past decade or so have supported
the hypothesis that Th1 cells are associated with the
stable lesion and Th2 cells are associated with disease progression (5, 16, 67, 72, 126, 143, 175, 182,
209, 240). However, other studies have reported a
predominance of Th1-type cells or reduced Th2 responses in diseased tissues (54, 191, 232). Recently,
the involvement of both Th1 and Th2 cells in periodontal disease in humans (19, 68, 78, 113, 158, 179,
248, 257) and in a mouse model (77, 84) has been
suggested. However, while showing cytokine patterns reflecting both subsets in inflamed gingival
tissues, Yamamoto et al. (257) conceded that a predominant expression of Th2 cytokines could contribute to the induction of high B-cell responses in
local disease sites. Indeed, in recent years several
reports have established that Th2 responses are
associated with periodontitis. One of these studies
demonstrated that peripheral blood mononuclear
cells from patients with so-called early-onset periodontitis (probably what is now recognized as
aggressive periodontitis) expressed reduced interferon-c protein and decreased interferon-c and IL-2
messenger RNA in response to mitogens, indicating
reduced Th1 responses, while higher IL-5 and
granulocytemacrophage colony-stimulating factor
were produced by cells from chronic periodontitis
patients, suggesting increased Th2 responses (209).
More significantly, an investigation of the activity of

The role of T cells in periodontal disease

P. gingivalis cysteine proteases found that these

gingipains hydrolyzed IL-12, thereby reducing IL-12induced interferon-c production by CD4 cells. It was
concluded that inactivation of IL-12 by the gingipains would therefore favor Th2 cells with disease
progression (261). Significantly, lower levels of IL12p70 produced by peripheral blood cells from periodontitis patients after stimulation with Escherichia
coli lipopolysaccharide have also been reported (65).
Whether E. coli or P. gingivalis induces the same
response with respect to IL-12, or whether plaque
bacteria, in particular those associated with periodontitis, down-regulate the systemic response as
found in the early studies two to three decades ago is
not certain. The results of the early studies could,
however, be explained by the down-regulation of IL12 and therefore of Th1 responses and hence IL-2mediated proliferation. Finally, the numbers of
immunoglobulin G4-positive (IgG4+) B cells in the
gingival tissues have been shown to increase relative
to IgG2+ cells with increasing inflammation, indicating the influence of IL-4 and Th2 responses and
decreased interferon-c and Th1 responses in large
infiltrates in periodontal disease (86).
In 1995, a study showed that the majority of CD4
clones established from gingival tissues and raised
non-specifically using mitogen and IL-2 had Th2
phenotypes producing high levels of IL-4 and low
levels of interferon-c. However, the majority of CD8
clones produced equal amounts of IL-4 and interferon-c (248). A further study demonstrated two
subsets of CD8 clones, one of which produced high
levels of interferon-c but no IL-4 or IL-5 (Th1) and
mediated cytolytic activity. The other subset produced high levels of IL-4 together with IL-5 and
displayed no cytotoxicity but could suppress the
proliferative response of cytotoxic CD8 T-cell clones.
It was concluded that CD8 T cells might participate
in the local response by suppressing interferon-cproducing cells and favoring humoral immune
responses (249). A higher level of intracellular IL-4
produced by peripheral blood CD8 cells from highly
susceptible patients with severe periodontitis has
since been shown, further supporting a role for CD8
cells in periodontitis together with a shift towards a
type 2 function (174). However, Teng (236) recently
played down a role for CD8 cells in periodontal
disease by concluding that this subset does not participate directly in periodontal disease destruction
during disease progression. It was suggested that
these cells not only produce important cytokines for
both innate and adaptive immune responses but
also participate in lysis of bacteria-infected or

bacteria-damaged tissues and cells. Obviously with

the increased numbers of CD8 cells relative to CD4
cells in progressive lesions, the determination of the
functions of this subset is paramount in understanding the pathogenesis of periodontal disease.
It is likely that different T-cell subsets predominate
at different stages of disease and the inability to
determine disease activity clinically is a major limitation in all studies (168). However, it remains clear
that the balance of cytokines in inflamed periodontal
tissues is what determines whether the disease
remains stable or leads to progression and tissue
destruction (168). In this context, the control of Th1
and/or Th2 expression is fundamental to understanding the immunoregulatory mechanisms in
chronic periodontitis.

B cells in periodontal disease

There is no doubt that T cells play a fundamental role
in periodontal disease. They are the dominant cell
type in the cell-mediated (macrophage/lymphocyte)
response and are necessary for both specific antibody
production and polyclonal B-cell activation, which
has been cited as being significant in the pathogenesis of periodontal disease (20, 32, 53, 104, 141, 169).
However, polyclonal activators do not activate all B
cells. Approximately 30% of B cells may be stimulated with different antigens acting on different subpopulations. Further, the antibodies produced will
most likely be of low affinity and the memory
component may not be induced (238). While B-cell
activation in periodontitis could be the result of nonspecific polyclonal activation and/or specific induction of sensitized B cells, IgG production by gingival
cells from patients with adult periodontitis has been
shown to be reduced in comparison with peripheral
blood B cells from the same patients and this distinctiveness of the local B-cell response has been
suggested to be the result of the unique combination
of T cells in the gingival tissues of patients with
periodontal disease (135).
The inability of specific antibodies to eliminate the
causative organisms of periodontal disease could be
the result of a number of factors, including poor
antigenicity of the virulence determinants and elicitation of antibodies with poor anti-bacterial properties (212). High titers of specific antibodies to
P. gingivalis (147, 254) and A. actinomycetemcomitans
(63, 129, 147, 190) have been demonstrated in the
serum and gingival crevicular fluid of periodontal
disease subjects, although the reports with respect to

17

Gemmell et al.

disease activity are conflicting (15, 56, 157). Studies

on immunodominant antigens of P. gingivalis (43,
124, 176) and A. actinomycetemcomitans (29, 30, 57,
62) have also shown different patterns of immunoreactivity. The production of anti-P. gingivalis antibodies with different avidities in various forms of
periodontal disease has been suggested to reflect the
quality of the humoral response, which may affect
progression of the disease (153). Anti-A. actinomycetemcomitans (242) and anti-P. gingivalis antibodies
(154) with higher avidities have been suggested to
confer greater resistance to continued or repeated
infection. Non-protective low avidity anti-P. gingivalis antibodies may be incapable of effectively
mediating a variety of immune responses (131, 251).
During the chronic phase of the disease, the
antibody response has been suggested to be generally protective, facilitating bacterial clearance and
arresting disease progression (166). An increased
capacity of serum to opsonize P. gingivalis has been
shown to be a distinctive feature in patients with
past destructive periodontal disease (254). This may
be because of the ability of anti-P. gingivalis protease antibodies, which occur late in periodontitis
infections, to block the anti-opsonizing activity
against C3 and IgG (45). Opsonic IgG antibodies to
A. actinomycetemcomitans, which may facilitate
neutrophil-mediated phagocytosis and be protective
against this periodontopathic organism, have also
been demonstrated (13, 242). Repeated infection
with A. actinomycetemcomitans has been shown to
elicit an anti-leukotoxin antibody that protects
neutrophils from the leukocidal activity of the leukotoxin (242).
Therefore, if specific antibodies with high avidity
and protective IgG subclasses to immunodominant
antigens are formed, the infection may be cleared
and the disease will not progress. However, polyclonal B-cell activation by periodontopathic bacteria
and the production of non-specific and/or
low-avidity specific antibodies may not clear the
infection. Continued B-cell activation leads to the
production of high levels of IL-1 resulting in tissue
destruction. Dendritic cells may provide signals that
initially activate T cells, while B-cell presentation may
allow for further activation and clonal expansion of
these already activated cells. An allogeneic mixed
leukocyte reaction was used to show that activated B
cells could act as potent antigen-presenting cells in
the presence of P. gingivalis or A. actinomycetemcomitans, resulting in the production of high levels of
interferon-c and minimal IL-5 (139). Although other
cytokines such as IL-4 were not measured in this

18

study, there is evidence that B cells direct Th2 CD4+ T

cells whereas macrophages activate Th1 cells (reviewed in Ref. 22) providing support for the concept
of antigen-specific T-cell and B-cell activation leading to Th2 responses in the B-cell periodontitis
lesion.

Inhibition of innate immunity in

periodontitis
In the gingival sulcus, neutrophils form a barrier
between the epithelium and the plaque biofilm (9),
which in most cases prevents bacterial invasion of
the epithelium and underlying connective tissue (96).
Both P. gingivalis and A. actinomycetemcomitans
have been reported to be capable of invading epithelial cells and even the connective tissues in diseased sites (64, 125, 192). Significantly, P. gingivalis
has been shown to have direct effects on the host
innate immune responses (reviewed in Ref. 48). The
migration of neutrophils from the circulation into the
tissues has been shown to be inhibited by suppressing the expression of the neutrophil-binding adhesion molecule E-selectin on endothelial cells (47) and
by blocking neutrophil transmigration through oral
epithelium by inhibiting the epithelial cell production of the chemokine IL-8 (138). A mouse model also
demonstrated inhibition of neutrophil phagocytosis
of immune serum-opsonized P. gingivalis (85),
possibly as a result of the cleavage of complement
and immunoglobulins by the P. gingivalis proteases
that prevent opsonization and subsequent neutrophil
killing of the bacteria (133, 193, 194, 221). A. actinomycetemcomitans produces a protein that inhibits
neutrophil chemotaxis and hydrogen peroxide production (7, 8) as well as a cytolytic leukotoxin which
lyses susceptible target cells including neutrophils,
monocytes and T cells (142, 227, 228). Interestingly,
unlike P. gingivalis and A. actinomycetemcomitans,
a recent mouse model study demonstrated that
T. forsythia, which is also implicated in periodontal
disease progression, did not affect neutrophil
migration into T. forsythia-induced lesions (89) and
therefore may not inhibit innate immune responses.
Macrophages too may be targeted for inhibition
by P. gingivalis. P. gingivalis has been reported to
stimulate the production of IL-1b by B cells rather
than monocytes and, as discussed below, to affect
macrophage migration by inhibiting the production
of one of the major monocyte/macrophage chemokines, monocyte chemoattractant protein-1 (79,
80).

The role of T cells in periodontal disease

T-cell suppression in periodontitis

Cytokines
We have recently used microarray analysis to show
that in BALB/c mice, P. gingivalis has a powerful
down-regulatory effect on splenic CD4 and CD8 cells.
Only five and 28 genes respectively were up-regulated
in the two subpopulations and in contrast, close to
1200 genes were down-regulated in each subset.
P. gingivalis had separate effects on the two
sub-populations with overlap being limited to 20%.
While most of the down-regulated genes were concerned with metabolism, some coded for immune
response proteins. These included several chemokine-like factors, chemokine ligands, and chemokine
receptors, suggesting interference with the recruitment of selected leukocytes or their binding (Table 1,
Ref. 87). As stated above, P. gingivalis inhibits macrophage migration in humans by inhibiting the production of monocyte chemoattractant protein-1 (79).
Furthermore, decreased levels of the neutrophil
chemoattractant IL-8 and monocyte chemoattractant
protein-1 have been demonstrated in umbilical vein
endothelial cells challenged with P. gingivalis (118).
These studies are in contrast to a recent report that
found a more frequent and higher expression of
monocyte chemoattractant protein-1 and its receptor
CCR4 in gingival biopsies taken from patients with
chronic periodontitis, although these findings were
relative to biopsies from patients with aggressive
periodontitis (69) not to control healthy or gingivitis
tissue sections. However, P. gingivalis gene expression for colony-stimulating factor 1 receptor, which
regulates the proliferation and differentiation of
monocyte/macrophage precursors (252), was also
down-regulated (87). Stimulatory DNA including
lipopolysaccharide has been shown to stop the
growth of murine marrow-derived macrophages
proliferating in colony-stimulating factor 1 by downmodulating surface colony-stimulating factor 1
receptor expression (196). No increase in macrophage numbers and little evidence of macrophage
activation have been demonstrated in advanced
periodontitis compared with minimally inflamed
tissues (35), suggesting that macrophages may have
protective effects in the stable lesion which are
abrogated in the advanced destructive lesion by
P. gingivalis.
Another gene down-regulated by P. gingivalis
codes for the cytokine receptor IL-17R (87). IL-17Rdeficient mice have a defect or display a significant
delay in neutrophil recruitment into infected sites

resulting in susceptibility to infection (114), which

may account partly for the reported inhibition of
neutrophils in the P. gingivalis-induced lesion in
mice (75). In contrast to the study in mice, IL-17
expression has been shown to be up-regulated in
human periodontitis tissue (165). This finding was
supported by the gene expression profile of T-cell
clones established from periodontitis patients where
51% of gingival T-cell clones expressed IL-17 compared with only 11% of peripheral blood T-cell clones
(105). In addition, stimulation of peripheral blood
mononuclear cells by P. gingivalis antigen enhanced
not only transcription but also translation of the
IL-17 gene (165). As IL-17 is capable not only of
inducing IL-6 in gingival fibroblasts but also of
enhancing the humoral immune response as well as
the inflammatory response, the balance between the
production of IL-17 and expression of its receptor
further reflects the fact that cytokines cannot be
studied in isolation and that it is the balance of
cytokines that is fundamental in disease expression.
Further genes down-regulated in the microarray
study included those which code for myeloperoxidase, peptidoglycan recognition protein, CD14, tolllike receptor 1 (TLR1) and toll interacting protein
(87). Myeloperoxidase is produced by macrophages
and neutrophils and participates in the respiratory
antimicrobial defense system (151). Peptidoglycan
recognition proteins, which are also critical for innate
immune responses, bind peptidoglycan in bacterial
cell walls and are involved in the killing and degradation of cell wall components and the initiation of
host defense reactions (144). CD14 is expressed
mainly by macrophages and plays a central role in
innate immunity as a receptor for bacterial lipopolysaccharide (61). Lipopolysaccharide also stimulates the innate immune response through TLR4.
TLR1 has been found to be physically associated with
TLR4 and has been demonstrated to have the capacity to abrogate TLR4 signaling and thus prevent innate responses to lipopolysaccharide (217). TLR1 has
also been shown to associate with TLR2 to recognize
native mycobacterial lipoprotein as well as other
lipopeptides (233). A recent study reported that
the Th1 cytokines interferon-c and granulocyte
macrophage colony-stimulating factor enhanced
TLR1 expression while the Th2 cytokine IL-4 downregulated TLR2 expression in monocytes and dendritic cells (123). Furthermore, toll-interacting protein
has been demonstrated to co-immunoprecipitate
with TLR2 and TLR4 and may be an important constituent of both the TLR2 and TLR4 signaling pathways (28). Overall, these results support other data

19

Gemmell et al.

Table 1. Gene expression changes in Porphyromonas gingivalis-activated CD4 and CD8 cells
Gene title

Gene symbol

CD4

CD8

CD4

CD8

Chemokine-like factor

Cklf

Chemokine-like factor super family 3

Cklfsf3

Chemokine-like factor super family 7

Cklfsf7

Chemokine (C-C motif) ligand 2

Ccl2

Chemokine (C-C motif) ligand 9

Ccl9

Chemokine (C motif) receptor 1

Xcr1

Chemokine (C-C motif) receptor 2

Ccr2

Chemokine (C-C motif) receptor 3

Ccr3

Chemokine (C-X-C motif) receptor 6

Cxcr6

Colony-stimulating factor 1 receptor

Csf1

Colony-stimulating factor 2 receptor, a, low-affinity

(granulocyte-macrophage)

Csf2ra

Interferon-c receptor 2

Ifngr2

Interleukin-1b

Il1b

Interleukin 1 family, member 9

Il1f9

Interleukin-1 receptor-associated kinase 4

Irak4

Interleukin 2 receptor c chain

Il2rg

Interleukin 6 receptor a

Il6ra

Interleukin 6 signal transducer

Il6st

Interleukin 7 receptor

Il7r

Interleukin 10 receptor b

Il10rb

Interleukin 16

Il16

Interleukin 17 receptor

Il17r

Interleukin 17 receptor B

Il17rb

Interleukin 18

Il18

Interleukin 18 receptor accessory protein

Il18rap

Transforming growth factor b1

Tgfb1

Transforming growth factor b-induced

Tgfbi

Transforming growth factor b receptor II

Tgfbr2

CD19 antigen

Cd19

CD22 antigen

Cd22

CD79A antigen (immunoglobulin-associated a)

Cd79a

CD79B antigen

Cd79b

Fc receptor, IgE, high affinity I, c polypeptide

Fcer1g

Fc receptor, IgE, low affinity II, a polypeptide

Fcer2a

Fc receptor, IgG, high affinity I

Fcgr1

Cytokines, chemokines, related factors, cytokine receptors

Ig binding/B-cell immunity

20

The role of T cells in periodontal disease

Table 1. Continued
Gene title

Gene symbol

CD4

CD8

CD4

CD8

Fc receptor, IgG, low affinity Iib

Fc receptor, IgG, low affinity III

Fcgr2b
Fcgr3

)
)

)
)

+
+

+
+

Similar to immunoglobulin c-2a heavy chain

Igh-1a

Immunoglobulin heavy chain 4 (serum IgG1)

Igh-4

Immunoglobulin heavy chain 6 (heavy chain of IgM)

Igh-6

Immunoglobulin heavy chain (gamma polypeptide)

Ighg

Immunoglobulin j chain variable 21 (V21) /// Anti-c-erbB-2/

p185 monoclonal antibody SER4 heavy chain variable region

Igk-V1

Immunoglobulin kappa chain variable 32 (V32)

Igk-V32

immunoglobulin lambda chain, variable 1

Igl-V1

CD2 antigen (cytoplasmic tail) binding protein 2

Cd2bp2

CD3 antigen, f polypeptide

Cd3z

CD8 antigen, a chain

Cd8a

CD8 antigen, b chain 1

Cd8b1

T-cell receptor b, variable 13

Tcrb-V13

T-cell receptor b, variable 13 /// Similar to TCRBV7S1

Tcrb-V13

T-cell receptor b, variable 13 /// T-cell receptor b,

joining region

Tcrb-V13 ///
Tcrb-J

T-cell receptor c, variable 4

Tcrg-V4

b2-microglobulin

B2m

CD1d1 antigen

Cd1d1

CD86 antigen

Cd86

ICOS ligand

Icos

Histocompatibility 2, class II antigen A, a

H2-Aa

Histocompatibility 2, class II antigen A, b1

H2-Ab1

Histocompatibility 2, class II antigen E a

H2-Ea

Histocompatibility 2, class II antigen E b

H2-Eb1

Histocompatibility 2, class II, locus DMa

H2-DMa

Histocompatibility 2, class II, locus Mb1 ///

histocompatibility 2, class II, locus Mb2

H2-DMb1 ///
H2-DMb2

Histocompatibility 2, class II, locus Mb2

H2-DMb2

Histocompatibility 2, O region a locus

H2-Oa

Histocompatibility 28

H28

Human leukocyte antigen-B associated transcript 8

Bat8

Ia-associated invariant chain

Ii

Histocompatibility 2, T region locus 23 ///

RIKEN cDNA C920025E04 gene

H2-T23 ///
C920025E04Rik

histocompatibility 2, T region locus 24

H2-T24

T cell immunity

Antigen presentation/major histocompatibility complex

21

Gemmell et al.

Table 1. Continued
Gene title

Gene symbol

CD4

CD8

CD4

CD8

Complement component 1, q subcomponent

binding protein

C1qbp

Complement component 1, q subcomponent,

a polypeptide

C1qa

Complement component 1, q subcomponent,

b polypeptide

C1qb

Complement component 1, q subcomponent,

c polypeptide

C1qg

Complement component 3

C3

Complement component 5, receptor 1

C5r1

Complement component 6

C6

CD14 antigen

Cd14

Myeloperoxidase

Mpo

Peptidoglycan recognition protein 1

Pglyrp1

Toll interacting protein

Tollip

Toll-like receptor 1

Tlr1

a disintegrin and metalloprotease domain 8

Adam8

a disintegrin and metalloprotease domain 10

Adam10

a disintegrin and metalloproteinase domain 17

Adam17

a disintegrin and metalloproteinase domain 19 (meltrin b)

Adam19

Integrin a4

Itga4

Integrin a6

Itga6

Integrin aL

Itgal

Integrin aM

Itgam

Integrin aV

Itgav

Integrin aX

Itgax

Integrin b2

Itgb2

Integrin b2-like

Itgb2l

Integrin b4 binding protein

Itgb4bp

Matrix metalloproteinase 9

Mmp9

Procollagen, type III, a1

Col3a1

Procollagen, type XIV, a1

Col14a1

Syndecan 3

Sdc3

Tissue inhibitor of metalloproteinase 2

Timp2

Intercellular adhesion molecule 2

Icam2

Platelet/endothelial cell adhesion molecule 1

Pecam1

Selectin, lymphocyte (l-selectin)

Sell

Innate immunity

Extracellular matrix and cell adhesion molecules

22

The role of T cells in periodontal disease

Table 1. Continued
Gene title

Gene symbol

CD4

CD8

CD4

CD8

Selectin, platelet (p-selectin) ligand

Selpl

Vascular cell adhesion molecule 1

Vcam1

Ostf1

Elastase 1, pancreatic

Ela1

Elastase 2

Ela2

Elastase 3B, pancreatic

Ela3b

Bone metabolism
Osteoclast stimulating factor 1
Wound healing

Reproduced from Gemmell et al. (87).

demonstrating that P. gingivalis evades host innate

immune responses.
P. gingivalis also down-regulated a number of
genes encoding cytokines or cytokine receptors in T
cells (87). These included the genes for IL-1b, IL-1
family 9 and IL-1R-associated kinase 4 (IRAK-4). IL-1
is a principal mediator of inflammatory responses
acting on many cell types and is itself produced by
many different cells, including macrophages, endothelial cells, B cells, fibroblasts, epithelial cells,
astrocytes, and osteoblasts in response to microorganisms, bacterial toxins, complement components or tissue injury (52). One of the most important
actions of IL-1 is its induction of other cytokines
(164). IL-1 is the most potent known inducer of bone
demineralization (219) as well as of major changes in
the connective tissue matrix (180). However, while
P. gingivalis depressed the gene for IL-1b in T cells,
it has, as stated above, been shown to induce an
increased percentage of peripheral blood B cells from
periodontitis patients to produce IL-1b compared
with macrophages (73). Since macrophages are not a
dominant feature of the advanced lesion (35) and
suppressed cell-mediated immunity is associated
with advanced periodontitis (25, 106), B cells may be
the major source of IL-1 in periodontitis.
One of the major effects noted in the microarray
study apart from suppression of T-cell function, was
the shift away from Th1 responses (87). IRAK is
recruited to the IL-1R complex on IL-1 stimulation
and is required for optimal transduction of IL-1-induced signals (136). However, more interestingly,
interferon-c production and Th1 cell proliferation
have been shown to be severely impaired in IRAK-4deficient mice (223). P. gingivalis also down-regulated the gene coding for interferon-c receptor 2 in CD8

cells. T cells in mice that are deficient in this receptor

were found to have a defect in Th1 differentiation
leading to lower amounts of interferon-c in response
to antigen challenge, with an alteration in interferonc-induced immunoglobulin class switching in B cells
(134). A study on the effect of tobacco smoke on
human peripheral blood cells by microarray analysis
found a significant depression in the gene for interferon-c receptor 2 as well as that for chemokine
receptor 2 (188), so that a subject with P. gingivalisinduced periodontitis who was also a smoker may
well have reduced interferon-c responses.
Two other genes down-regulated by P. gingivalis
included IL-18 and IL-18R accessory protein
(IL-18Rap) (87). IL-18 is a member of the IL-1 family
(90) and the IL-18Rap is required for IL-18 signaling
(24). IL-18 can act with IL-12 to promote the generation of interferon-c-producing Th1 cells (160),
suggesting again that P. gingivalis promotes the
down-regulation of this T-cell subset. However,
another study reported higher concentrations of IL-18
in gingival biopsies from sites with a probing depth
>6 mm compared with healthy sites although IL-12
concentrations were significantly lower (108). This
combination would also lead to reduced Th1
responses. Yet another study reported a higher production of IL-18 by whole blood cells from patients
with periodontitis although the stimulus was E. coli
lipopolysaccharide (65). Although this study also
showed reduced IL-1b in response to E. coli, the lipopolysaccharides from this bacterium and from
P. gingivalis appear to have differential effects.
The gene coding for the IL-10Rb was down-regulated by P. gingivalis in CD4 cells (87), suggesting an
inability of these cells to respond to IL-10. IL-10 has
many biological functions including the limitation

23

Gemmell et al.

and termination of inflammatory responses and

regulation of proliferation and differentiation of
immunocompetent cells, including T and B cells and
antigen-presenting cells (reviewed in Ref. 6). The nonresponsiveness of T cells to P. gingivalis has recently
been shown, although peripheral blood B cells did
proliferate and high levels of IL-10 were produced by
monocytes. IL-10 itself could induce B-cell proliferation and it was suggested that P. gingivalis may play
a role in polyclonal B-cell activation associated with
periodontal disease via a macrophage-dependent
IL-10 route (34). However, as previously stated,
macrophages are most likely not activated in
periodontitis lesions (35), suggesting the possible
importance of the lack of this immunosuppressive
cytokine in periodontitis lesions. However, one of the
important effects of IL-10 is its direct inhibitory
effects on interferon-c production (49) and in
humans, IL-10 promotes Th2 responses while suppressing delayed-type hypersensitivity reactions and
other Th1-cell-mediated responses (103). While the
microarray study indicated that CD4 cells would not
respond to IL-10 because of the down-regulation of
the IL-10Rb gene, the down-regulation of the other
genes, including IRAK-4, interferon-c receptor 2, IL18 and IL-18Rap, would still suggest a swing away
from Th1 responses.
The microarray study also demonstrated the downregulation by P. gingivalis of the gene encoding the
IL-2Rc chain in CD8 cells (87). The IL-2Rc is shared
by receptor complexes used by IL-2 and other
cytokines including IL-4, IL-7, IL-9 and IL-15, all of
which are involved in lymphocyte development and/
or activation. IL-2Rc is physically associated with
JAK3 tyrosine kinase (which was also down-regulated
in CD4 cells), and this molecular pair may be considered to be the trigger of the signaling cascades.
X-linked severe combined immunodeficiency in
humans is caused by mutations in the IL-2Rc gene
that result in absent T cells and non-functional B cells
(10). Prevotella intermedia strains have been shown
to not only inhibit T-cell and B-cell proliferation in
response to mitogens and antigens, but to inhibit
IL-2R expression on T cells (208). The down-regulation of the IL-2Rc chain may well support studies
demonstrating a lack of IL-2 production and reduced
IL-2R expression by T cells in patients with a reduced
autologous mixed lymphocyte reaction (116, 203).
P. gingivalis also induced the down-regulation of
the genes coding for transforming growth factor-b1
and the transforming growth factor-b2 receptor (87).
Transforming growth factor-b is a pleiotropic cytokine with transforming growth factor-b receptors

24

being expressed on most cell types (88); down-regulation of the cytokine and its receptor would have
wide-ranging effects (87). A mouse model in which
transforming growth factor-b was blocked specifically
in T cells, demonstrated that T-cell homeostasis requires transforming growth factor-b signaling (88).
Hence, the ability of P. gingivalis to down-regulate
the genes coding for this cytokine further illustrates
the dynamic balance that may be occurring between
the plaque biofilm and the host.
Another study in mice showed that transforming
growth factor-b is important for B-cell development
and that B-cell progenitors are differentially affected
according to their stage of differentiation (112).
Transforming growth factor-b is also involved in all
aspects of wound healing entailing inflammation,
re-epithelialization, matrix formation, and remodeling (3). It is produced locally at the site of resorption
of bone and has been shown to initiate new bone
formation (33). The down-regulation of transforming
growth factor-b in T cells confirms an earlier study
which demonstrated that more transforming growth
factor-b may have been produced by peripheral
blood mononuclear cells in culture in the absence of
stimulatory bacteria (72).

Surface membrane antigens

As well as down-regulating a number of cytokinerelated genes, P. gingivalis also down-regulated
several genes encoding proteins which directly affect
T-cell function (87). These included CD2-binding
protein 2 expression. This protein binds to a site
within the cytoplasmic region of CD2 and overexpression of the isolated protein enhances IL-2
production on cross-linking of CD2 in Jurkat T cells
(163). The cell adhesion molecule CD2 is expressed
by T cells and recognized by CD48 in mice and CD58
(lymphocyte function-associated antigen-3; LFA-3) in
humans (253). CD2CD48 interactions have been
shown to be critical for the production of sufficient
IL-2 and interferon-c to induce the differentiation of
CD8+ cells into functional cytotoxic cells (155). The
CD2 molecule is expressed on the majority of murine
lymphocytes and plays a regulatory role in antigenspecific responses via the T-cell receptor (167, 243).
The absence of CD2 on murine T-cell receptor a/b+ T
cells has been shown to co-segregate with nonresponsiveness (243). CD2+ T cells have been demonstrated in the gingival tissues of patients with
chronic periodontitis (91) although a lower percentage of positive cells has been reported compared with
peripheral blood T cells (74). Taken together, these

The role of T cells in periodontal disease

results suggest an increase in non-responsive T cells

in the gingival tissues as a result of the down-regulation of the CD2 binding protein 2 by P. gingivalis in
periodontitis. Yet again, they also indicate a swing
away from the Th1 cytokines IL-2 and interferon-c.
The T-cell receptor is a complex composed of the
antigen-binding heterodimer (a/b or c/d chains) and
a signal transducing complex consisting of the CD3
dimers (CD3 c/e and CD3 d/e) and the T-cell receptor
f homodimer (95). This T-cell receptorCD3 complex
plays a key role in antigen recognition, T-cell activation, and triggering antigen-specific responses (23).
The microarray study demonstrated that the gene
coding for CD3f was down-regulated by P. gingivalis
(87). T cells from patients with systemic lupus
erythematosus display T-cell receptor f chain aberrations as well as defective IL-2 production (162),
suggesting another association between reduced IL-2
production and P. gingivalis-induced periodontitis.
The cell surface glycoprotein CD8 functions as a
co-receptor with the T-cell receptor for interaction
with major histocompatibility complex class I molecules (50) CD8 exists as homodimers of a polypeptide
chains and heterodimers of a and b chains and while
the CD8a chain binds to major histocompatibility
complex class I, the function of CD8b, for which there
are two genes, CD8b1 and CD8b2, is not as clear (51,
161). Gemmell et al. (87) demonstrated down-regulation of the genes for CD8a and b1 chains in both
CD4 and CD8 cells. It has recently been shown that
CD8 is expressed on CD4 cells in rats and these cells
helped in primary humoral responses and produced
mainly Th1 cytokines (115). Therefore, it follows that
in periodontitis, Th1 cytokines produced by helper T
cells expressing CD8 may be decreased. However, a
down-regulation of CD8 responses induced by P.
gingivalis is at odds with reports showing a decrease
in the CD4 : CD8 ratio in periodontitis biopsies
compared with peripheral blood and healthy/gingivitis tissue (170, 234).

Cell adhesion molecules

Leukocytes migrate into the tissues from the peripheral circulation and the first step in this migration
is binding to endothelial cell adhesion molecules.
These endothelial cell adhesion molecules are
expressed on endothelial cells as well as on leukocytes and a recent report showed that while LFA-1/
endothelial cell adhesion molecule-1 binding resulted in the production of IL-10, LFA-1/endothelial cell
adhesion molecule-2 binding induced a stronger
secretion of the Th1 cytokine tumor necrosis factor-a

(21). Adhesion molecules are therefore important

factors in determining the homing of leukocyte subsets as well as imparting other functional roles such
as differential cytokine production. The genes encoding endothelial cell adhesion molecule-2 and several
integrins were down-regulated in mice by P. gingivalis, particularly in the CD8 cells (87). Integrins
mediate the migration of leukocytes through the
extracellular matrix and induce signals that direct
different cellular signaling pathways (44). Interestingly, the b2 integrin subunit of LFA-1 (CD18) was
down-regulated in CD8 cells, which would result in
the abrogation of the LFA-1/endothelial cell adhesion
molecule-2 pathway. Overall these results may indicate a role for P. gingivalis in down-regulating Th2
cytokines.

Antigen presentation
As already stated, P. gingivalis and A. actinomycetemcomitans are capable of invading epithelial cells
(64, 192). Keratinocytes expressing class II molecules
have been reported in inflamed sites of gingival tissues (204), suggesting that in humans, gingival keratinocytes can present antigens to the underlying
lymphocytes (189). An animal model has only
recently shown that rat gingival epithelial cells treated with interferon-c and A. actinomycetemcomitans
express major histocompatibility complex class II
molecules and the co-stimulatory molecule CD80
and can stimulate A. actinomycetemcomitans-specific
CD4 cells to proliferate (145). However, it is also
possible that Langerhans cells in the gingival epithelium (82, 109) may also present P. gingivalis
antigens. Furthermore, different dendritic cell subsets have been demonstrated in the gingival tissues
and have been shown to associate with clusters of
CD4 cells, suggesting that antigen presentation to T
cells may occur in the connective tissues (109). While
peptide antigens are recognized in an major
histocompatibility complex-restricted manner, lipidcontaining antigens such as lipoprotein and lipopolysaccharide are recognized in a CD1-restricted
manner. Cells expressing all isoforms of CD1, namely
CD1a, b, c, and d, are present in periodontitis tissue
and the total expression of CD1 is equivalent to that
of CD83, a marker of mature dendritic cells. This
suggests the potential importance of lipid antigens in
chronic periodontitis (2).
It is however, becoming apparent that T cells
themselves can present antigen. Resting cattle CD4
cells from calves immunized with ovalbumin or respiratory syncytial virus were found to proliferate in

25

Gemmell et al.

response to c/d T cells pulsed with antigen-presenting cells expressing high levels of major histocompatibility complex class II molecules and synthesizing
the co-stimulatory molecule CD80 (40). Another
study showed similar results using circulating
porcine c/d T cells. Peripheral blood from ovalbumin-immunized pigs depleted of all conventional
antigen-presenting cells were able to proliferate in
response to antigen and this response was abolished
after depletion of c/d T cells and anti-major histocompatibility complex class II or anti-CD4 antibodies
(230). An earlier study in humans demonstrated that
tetanus antigen-specific T-cell clones pre-incubated
with antigen followed by irradiation could present
antigen and initiate proliferation by autologous
cloned T cells. Again this antigen presentation was
abrogated by treatment with anti-human leukocyte
antigen-DR or anti-tetanus antibodies. Autologous
peripheral blood resting T cells or phytohemagglutinin-activated T-cell blasts could not present antigen
to responder cloned T cells (37). More recently, it has
been reported that human T cells can acquire large
quantities of major histocompatibility complex class
II molecules from various types of antigen-presenting
cells in an antigen-independent manner and this
required direct cell-to-cell contact and interaction of
adhesion molecules. The newly acquired major histocompatibility complex class II molecules were
capable of presenting antigen to T helper cells, suggesting that T cells interact with other T cells to
regulate immune responses by presenting major
histocompatibility complex class II peptide complexes obtained from nearby antigen-presenting cells
(241). A further study showed that lamina propria T
cells from actively inflamed inflammatory bowel
disease mucosa expressed large amounts of major
histocompatibility complex class II molecules and
CD86 and could stimulate allogeneic naive peripheral
blood T-cell proliferation. This process was reduced
by the addition of IL-10. It was suggested that this
interaction between T cells could contribute to the
perpetuation of inflammation (59).
The study by Gemmell et al. (87) showed that
mRNA for certain class I and II molecules and the
Ia-associated invariant chain were down-regulated in
both CD4 and CD8 cells. The H-2 major histocompatibility complex of mice encodes two functional
proteins, Aa Ab (A) and Ea Eb (E) (226). Efficient
loading of class II molecules with peptides requires
the invariant chain and the class II-like molecule
H2-M (now H2-DM) (122). Cells from mice devoid
of the invariant chain show aberrant transport of
major histocompatibility complex class II molecules,

26

leading to reduced levels of class II complexes at the

surface which do not have the typical compact conformation indicative of tight peptide binding (246).
Because of the physical association of H2-O with
H2-M and the co-localization in class II+ vesicles, it
has been suggested that H2-O may have a related
function in peptide exchange (173). Generally, downregulation of these genes would lead to impairment
of antigen presentation functions. However, the
extent of T-cellT-cell interaction in the gingival
tissues is at this stage unclear.
The suggestion of impairment of antigen presentation functions in P. gingivalis-induced periodontitis
was also reflected in the down-regulation of the
genes for CD86 (a ligand of the major co-stimulatory
CD28) and inducible co-stimulatory molecule ligand
(a member of the CD28 family). Activation of T cells
leading to cytokine production requires a signal
transduced through the T-cell receptor as well as a
second signal transduced by a co-stimulatory molecule (70). CD28 is the major co-stimulatory signal
receptor for T cells and its natural ligands are CD80
(B7-1) and CD86 (B7-2), which are expressed either
constitutively or after activation on antigen-presenting cells (1). Inducible co-stimulatory molecule, a
member of the CD28 family, is expressed by activated
T cells and binds with its ligand, which is constitutively expressed on B cells. Interaction leads to
differentiation of B cells to plasma cells (127), suggesting that antigen-specific activation of B cells in
periodontitis may be suppressed by P. gingivalis.
Activated monocytes, B cells and dendritic cells
express B7 molecules (111). Macrophages constitutively express low levels of CD86, CD80 being
induced after treatment with interferon-c. CD86
expression is also low on B cells until activation,
which induces a rapid up-regulation of these molecules (107). The percentage of CD86+ B cells and
macrophages has been shown to be significantly
higher than the percentage of CD80+ macrophages in
gingival tissue sections (81). Another study showed
that CD86 was up-regulated mostly on B cells isolated from periodontitis lesions and that a number of
periodontopathic bacteria including P. gingivalis
up-regulated CD86 on B cells in vitro (139).
It is now becoming clear that T cells also express
co-stimulatory molecules. Activated human peripheral blood T cells, CD4 and CD8 clones and natural
killer clones have been shown to express B7 molecules (11). Anti-CD28 antibodies or CTLA4-Ig fusion
protein have been demonstrated to inhibit the
proliferation of specific T-cell clones in response
to T cells acting as antigen-presenting cells or

The role of T cells in periodontal disease

proliferation of peripheral blood mononuclear cells

in a primary allostimulation with activated T cells as
stimulator cells. B7 was also found to be expressed on
subsets of freshly isolated activated CD4 or CD8 cells
from some individuals infected with human immunodeficiency virus or from others with autoimmune
diseases, although T cells from healthy individuals
did not express B7 (256). Hirokawa et al. (98)
suggested that B7 molecules functioned as co-stimulatory molecules on T cells and played a role in
interactions between T cells leading to clonal
expansion of activated T cells. Another study has
shown that memory CD4 cells express CD86 while
naive CD4 cells do not, although the positive memory
cells co-stimulated the naive T cells with anti-CD3
antibodies to induce IL-2 production. The naive cells
were shown to express CD86 after co-stimulation
with CD86 and T-cell receptor ligation (92). A mouse
model showed that when T-cell donors from CD80/
CD86-deficient mice were used for allogeneic transplant recipients, graft-vs.-host disease accelerated
compared with wild-type T cells. On the other hand,
T cells from CD86 transgenic mice that overexpressed CD86, mediated the reduced graft-vs.-host
disease mortality. This study demonstrated the
importance of T-cell-associated B7 molecules as
negative regulators of immune responses (235). The
significance of down-regulation of CD86 on T cells in
periodontal disease is currently unknown.

Autoimmunity: natural killer T

cells
Mouse CD1d1 is a member of the CD1 family of
evolutionarily conserved major histocompatibility
complex antigen-like molecules (110). Unlike the
classical major histocompatibility complex products
that bind peptides, mouse and human CD1d molecules present glycolipid antigens such as a-galactosylceramide to CD1d-restricted natural killer T cells.
The use of CD1d knockout mice has demonstrated an
inability to clear metastatic tumors and a-galactosylceramide was able to inhibit disease in diabetes-prone
non-obese diabetic mice, suggesting a critical role for
CD1d-dependent T cells in various disease conditions
(102). Another study showed that CD1 expression
increased on antigen-presenting cells in Listeriainfected mice and the use of anti-CD1 antibody
reduced transforming growth factor-b2 levels while
increasing IL-12 and interferon-c at disease onset. The
results pointed to a regulatory role for CD1-reactive
cells in the immune response to Listeria (224).

Mouse natural killer 1 cells constitute a subset of

T-cell receptor ab+ T cells that express natural killer
surface receptors. They are thought to play an
immunoregulatory role because of their ability to
secrete IL-4 within minutes of primary activation
(17), although another report demonstrated a rapid
production of both IL-4 and interferon-c in mice after
treatment with a-galactosylceramide (211). A unique
feature of their T-cell receptor repertoire is the
expression of an invariant T-cell receptor chain,
Va14-Ja281 in mice (18) and Va24-JaQ in humans
(177). A recent immunohistological study examined
natural killer T cells in periodontal disease and found
that the frequency of Va24-JaQ T-cell receptorexpressing T cells was higher in periodontitis lesions
than in gingivitis tissues or peripheral blood. The
natural killer T cells also appeared to associate with
CD1d+ cells and it was suggested that these cells play
a regulatory role in periodontal disease (258).
Autoimmunity has been suggested to be a feature
of periodontal disease. Cross-reactivity of human
heat-shock protein 60 and P. gingivalis GroEL, which
is a bacterial homologue, has been shown in periodontal disease (66, 225). Heat-shock protein
60-specific, as well as P. gingivalis cross-reactive, T
cells have also been demonstrated to accumulate in
periodontitis lesions (259). Taken together these data
suggest that both a humoral and a cell-mediated
specific immune response to heat-shock protein 60
may be important in the disease process. Additionally, anti-collagen type l and lll antibodies have been
demonstrated in the gingivae of periodontitis patients (99) and collagen type 1-specific T-cell clones
have been identified in inflamed tissues of periodontitis patients (248).
The study by Yamazaki et al. (258) suggests that an
immune response to autoantigens such as collagen
type I or heat-shock protein 60 may be well
controlled by natural killer T cells. A relationship
between a deficiency in natural killer T cells and
autoimmune diseases has been cited in mice (150,
231). An impairment of the subtle balance could be
involved in the pathogenesis of periodontal disease
(Fig. 2) The results however, did show increases of
natural killer T cells in periodontitis, suggesting a
functional role for these cells and because of their
ability to secrete rapid amounts of cytokines, they
may influence the T helper cytokine response. In
support of the above findings (258), CD1d is the most
prominent CD1 molecule in periodontitis and the
CD1d-expressing cells increased with increasing
number of invariant natural killer T-cell infiltration
(2). It is becoming clear that both bacterial and

27

Gemmell et al.

Indirect
mechanism

Microbial
components
(lipopolysaccharide,
lipoteichoic acid, etc.)

TLRs

Dendritic
cell

Increased
synthesis of these
molecules

cytokines

CD1d
NKT cell

Endogenous
glycolipid

cytokines

B
Direct mechanism
Microorganisms

Dendritic
cell
microbial glycolipids

CD1d
CD1 reactive T
cell (NKT ells)

cytokines

Fig. 2. Putative roles of autoimmune response and regulatory mechanisms in susceptible patients and non-susceptible patients. In susceptible patients (A), infection and
subsequent inflammation result in the up-regulation of
auto-antigens such as heat-shock protein 60 and collagen
type I and the activation of auto-reactive T and B cells
specific to those antigens. Although regulatory T cells are
induced in the lesion, their number and function may not
be sufficient to control immune pathology. In non-susceptible patients (B), on the other hand, the autoimmune
response stimulates scavenger cells to take up the
degenerated self-components resulting in acceleration of
the tissue repair process. These mechanisms may be well
controlled by regulatory T cells. Consequently, tissue
integrity is maintained and the stable lesion can be seen.

endogenous glycolipids presented by CD1d can be

recognized by human natural killer T cells but in
some instances, the recognition of bacteria by natural
killer T cells may be indirect (146) (Fig. 3). One study
suggested that Salmonella infection may lead to an
altered environment, where natural killer T cells are
stimulated by inflammatory cytokines in combination with CD1d-mediated presentation of autologous
ligands, induced in response to infection (27). This
scenario could also be applicable to chronic inflam-

28

CD1
glycolipid autoantigens
microbial glycolipids

Fig. 3. Indirect and direct mechanisms of CD1d-reactive

natural killer T-cell (NKT) activation. Microbial components such as lipopolysaccharide, lipoteichoic acid and
other lipopeptides can be recognized by TLRs resulting in
increased synthesis of endogenous glycolipid. Natural
killer T cells recognize endogenous glycolipids presented
by CD1d. Natural killer T cells are also stimulated by
inflammatory cytokines induced in response to infection
(A). Microbial glycolipid can also be directly presented by
CD1d molecule, resulting in the activation of natural killer
T cells (B).

matory periodontal diseases in which inflammatory

cytokines are up-regulated.
However, down-regulation of CD1d in murine T
cells by P. gingivalis has been demonstrated (87)
implying that even though there may be higher
numbers of natural killer T cells in periodontitis,
these may not be functional if T-cellnatural killer

The role of T cells in periodontal disease

T-cell interactions were a feature of periodontal disease. In addition to invariant natural killer T cells,
other phenotypes of regulatory T cells, possibly CD4+
CD25+ regulatory T cells, Th3 and Tr1 infiltrate and
may play roles in periodontal disease (159).
The role of autoimmunity in chronic inflammation
is still not clear. It is possible that autoimmunity is a
feature of all chronic inflammatory processes. In this
context it has been known for many years that gingival fibroblasts are able to phagocytose collagen
such that anti-collagen antibodies may facilitate this
phagocytosis and hence the removal of broken down
collagen. At the same time an anti-heat-shock protein
response may enhance the removal of dead and
dying cells such that these autoimmune responses
may be a natural part of chronic inflammation.
Control of these responses would therefore be
essential, hence the increase in regulatory natural
killer T cells in periodontal tissues. This concept
further illustrates that the role of T cells in periodontal disease may be one of immune homeostasis.
Further studies are clearly needed to test this hypothesis and to determine the role of regulatory T cells
in periodontal inflammation.

Bone loss
Do T cells have a role in tissue destruction in periodontal disease? It has been known for some time
that cells of the immune system can influence bone
cell function (132). Osteoclasts share a common
origin with cells of the macrophage/monocyte lineage and respond to and produce cytokines that
regulate cells of this lineage. Osteoblasts originate
from bone marrow stromal stem cells of mesenchymal origin and have the capacity to produce factors
that influence the lineage development of bone
marrow cells (132). Receptor activator of nuclear
factor-jB ligand (RANK-L), which is also known as
osteoprotegerin-L (OPG-L), regulates osteoclast differentiation and function (229). The receptor for
RANK-L/OPG-L is RANK (4) and a variety of cells
produce a decoy receptor OPG, which when released
by cells, binds RANK-L/OPG-L to prevent activation
of RANK (210). While these factors have potent
effects on osteoclast development, they also have
regulatory effects on immune cell function (132).
Results of a study on RANK-L/OPG-L-deficient mice
showed that this factor is critical in T-cell maturation
and T cells in these mice showed poor induction of
cytokines such as interferon-c, IL-2, and IL-4 in response to anti-CD3 and anti-CD28 (119). Increased

concentrations of RANK-L and decreased concentrations of OPG have been reported in the gingival
crevicular fluid from periodontitis patients compared
with control subjects and the ratio of RANK-L/OPG
was also significantly higher, suggesting that these
two factors contribute to alveolar bone destruction
in periodontal disease (152). A similar finding was
reported in another study with levels of RANK-L
being higher in active sites that were probably
associated with tissue destruction compared with
inactive sites (244). Interestingly, human gingival
fibroblasts were shown to express OPG rather
than RANK-L and OPG mRNA expression and production by gingival fibroblasts was augmented
by lipopolysaccharide stimulation. Supernatants of
lipopolysaccharide-stimulated fibroblasts reduced
the numbers of tartrate resistant acid phosphatasepositive cells generated by monocytes cultured in the
presence of RANK-L and macrophage colony-stimulating factor, suggesting the inhibition of monocyte-derived osteoclasts via an OPG pathway (156).
Gingival fibroblasts therefore may not play a role in
bone resorption in periodontal disease. Another
study by Liu et al. (130) supported the finding of
higher levels of RANK-L and lower levels of OPG in
advanced periodontitis. More significantly, RANK-L
mRNA was expressed mainly by inflammatory
lymphocytes and macrophages as well as proliferating epithelium in the vicinity of inflammatory cells.
Although both soluble and membrane-bound RANKL can be produced by activated T cells (119), the
frequency of RANK-L mRNA-positive gingival T-cell
clones was low but variable compared with the high
and constant frequency of other cytokines such as
interferon-c and transforming growth factor-b1
(105). This may reflect disease activity of the sites
from where the cells were extracted or the susceptibility of the patients from whom the tissues were
obtained.
CD4 knockout mice, but not CD8 knockout mice,
lose less alveolar bone in response to oral P. gingivalis infection than immunocompetent mice of the
same genetic background, suggesting that CD4 cells
may contribute to bone resorption (14). Experiments
in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice transplanted with human
peripheral blood lymphocytes from periodontitis
patients and orally challenged with A. actinomycetemcomitans also showed that human CD4 cells but
not CD8 cells or B cells were able to mediate alveolar
bone destruction (237). This study also showed that
A. actinomycetemcomitans stimulated the production
of OPG-L by CD4 cells, while inhibition of OPG-L

29

Gemmell et al.

function using OPG diminished bone destruction and

reduced the numbers of periodontal osteoblasts after
bacterial challenge. The authors acknowledged that
OPG-L produced by CD4 cells may not be the sole
inducer of increased alveolar bone destruction in
periodontal disease because injection of soluble OPG
for 4 weeks did not completely block this bone
destruction in vivo. An OPG-L-independent induction of osteoclast differentiation has been reported
(117). This study found that osteoclasts could be
generated from mouse bone marrow cells and this
was not inhibited by OPG.
As already stated, IL-1 has a major role in bone
resorption in periodontal disease and both IL-1 and
tumor necrosis factor-a have been reported to regulate the balance of OPG-L and OPG (100, 101) thereby
contributing to bone destruction independently of
cell-mediated immunity (237). In this respect, P. gingivalis was shown to down-regulate the gene expression for osteoclast stimulating factor 1 as well as for
IL-1b in CD4 cells (87), suggesting that P. gingivalisinduced T cells may not play a role in the bone
resorptive process in periodontal disease. However,
even though B cells were shown not to contribute to
A. actinomycetemcomitans-induced bone resorption
in mice (237), as discussed earlier, P. gingivalis
induced IL-1b production by B cells rather than
monocytes (73). Therefore, with increased numbers of
B cells associated with disease progression, a link
between B cells and alveolar bone destruction in
human periodontitis may be more than possible.

Connective tissue matrix

destruction
Connective tissue remodeling occurs in growth and
development and is regulated by the interplay of
cellcell and cellmatrix interactions involving the
production of enzymes, activators and inhibitors and
cytokines and growth factors (185). Proteinases such
as the metalloproteinases (MMPs) are key enzymes in
tissue degradation and this family of neutral proteases is part of a larger class of metalloproteinases
that include the ADAMS (disintegrin and metalloproteinase domain) (187). MMPs produced by resident cells including fibroblasts, macrophages, and
epithelial cells and also inflammatory cells have been
cited as playing roles in tissue destruction in periodontal disease (148, 195, 260) and are regulated by
tissue inhibitors of metalloproteinases (TIMP).
It has been suggested that tissue destruction in
disease processes may be the result of an imbalance

30

of metalloproteinases over tissue inhibitors (185).

The concentration of TIMP-1 in the saliva of patients
with periodontitis has been shown to be lower than
in the saliva of healthy subjects, while collagenase
activity was higher. Initial therapy resulted in reciprocal changes of TIMP-1 and collagenase levels.
Furthermore, collagenase in the healthy subjects
consisted mainly of procollagenase whereas in diseased patients, active collagenase was found predominantly (94). Also, greater collagenase activity
was found in the gingival crevicular fluid of periodontitis patients than in the fluid of control subjects
and the collagenase was demonstrated to be derived
mostly from neutrophils (245). MMP9 produced by
neutrophils was shown to be prominent not only in
the crevicular fluid but also in the gingival tissue
samples from patients with periodontitis (214, 250).
Latent MMP2 and MMP9 are expressed in the gingival tissues of patients with periodontitis; active
MMP2 was only detected in tissues associated with
clinical disease (121) although another study suggested a role for MMP9 in the gingival epthelial
response to periodontal infection (213, 214). Yet another study suggested a role for both MMP2 and
MMP9 in tissue destruction in periodontitis (140)
while Seguier et al. reported increased amounts of the
active form of MMP9 in gingival tissue specimens of
periodontitis patients (195). Recently it has been
reported that P. gingivalis and A. actinomycetemcomitans supernatants can activate MMP2 in human
periodontal ligament cells, although while A. actinomycetemcomitans induced a reduction in TIMP2
secretion, there was no change in the level of TIMP2
in the presence of P. gingivalis supernatants (239).
Although direct T-cell-derived metalloproteinases
have not been reported, our microarray study showed
that MMP9 and TIMP2 were down-regulated in CD4
cells (87).
The microarray study also demonstrated a downregulation of the gene for procollagen type III in CD4
cells. Whether or not the same is true for fibroblasts
remains to be determined. Both collagen type III and
fibronectin have been shown to be greatly diminished in inflamed gingiva (247), indicating a case for
P. gingivalis-induced type III collagen deficiency in
periodontitis. Transmission electron microscopy of
biopsies from patients with rapidly progressive periodontitis and from adult periodontitis patients
demonstrated the almost complete destruction of
collagen types l and lll in areas with leukocyte infiltration while collagen types V and Vl were dominant
(97). Another study correlated the number of
inflammatory cells with the area of collagen fibers

The role of T cells in periodontal disease

that was decreased in gingival connective tissues of

patients with severe periodontitis compared with
healthy controls. Second, increases in the amounts of
MMP1, MMP2, MMP3, and MMP9 and the active
form of metalloproteinase 9 were correlated with the
number of CD22+ B cells and CD68+ cells, which
would include macrophages and T-cell intracellular
antigen 1-positive cells (195), implicating T cells in
the production of metalloproteinases. However,
while P. gingivalis may down-regulate metalloproteinase 9 in T cells, metalloproteinase production by
other cells, including B cells, may be increased in
periodontitis.

Susceptibility to periodontal
disease
It is clear that variations in disease occur in individuals who harbor the same periodontal pathogens
in their dental plaque as well as in patients in whom
the bacterial composition varies (235). While periodontopathic bacteria and the inflammation they
provoke are essential for disease progression, environmental risk factors such as tobacco smoking,
psychosocial stress, and systemic diseases such as
diabetes modify the host response and may be
major determinants of the enormous variation in
susceptibility (172).
It also appears that genetic factors may determine
susceptibility or resistance to periodontal disease (12,
93). Results from family studies suggested that environmental factors might be major determinants of
variation in periodontitis, although twin studies
indicated that both environmental and genetic
factors influenced disease progression (149). Interestingly, although genetic predispositions to periodontitis may involve defects other than those of the
immune response, including defects in collagen,
cementum, and epithelium (93), genetic control of
the immune response in periodontal disease is significant because of the importance of immunity in
disease progression. In this respect, an animal model
study has shown that the CD4 cytokine response to
P. gingivalis depended on the H-2 haplotype (84),
indicating a strong genetic influence on T-cell
immunity to this periodontopathic bacterium.
To understand the extent to which the variation in
cytokine responses in periodontal disease may be
attributed to genetic determinants, genetic polymorphisms in cytokine genes have become an area of
research. Polymorphisms in the IL-1 cluster have
been a focus of attention since Kornman et al. (120)

demonstrated that genotype-positive individuals had

a 20-fold increased risk of developing severe periodontitis after the age of 40 than those individuals who
are genotype negative (120). A recent microbiological
study of IL-1-positive and IL-1-negative adults
showed that significantly higher counts of bacteria,
including T. forsythia, P. gingivalis, T. denticola as
well as others, were detected in periodontal pockets
>6 mm in depth in genotype-positive subjects than
in individuals who were genotype negative (216),
suggesting that there may be a correlation between a
tendency of genotype-positive people to harbor these
bacteria in their plaque. In a 5-year longitudinal
study on the progression of periodontal disease,
Cullinan et al. (41) showed that while there was no
direct effect of the IL-1 genotype on disease progression there were interactive effects between the
IL-1 genotype, the presence of P. gingivalis and disease and between IL-1 genotype, smoking, and disease such that the IL-1 genotype could be considered
as a secondary risk factor for periodontal disease.
This study was the first to show the interactions between bacteria, genetics, and environment in the
progression of periodontal disease. In their review on
cytokine gene polymorphisms in periodontal disease
Taylor et al. (235) suggested that apart from IL-1
polymorphisms, a role for cytokine gene polymorphisms and susceptibility to chronic periodontitis
have not been established, although understanding
cytokine regulation and immune regulation in periodontal disease remains of major concern.

Conclusion
Despite over 40 years of research into the immunology of periodontal disease the role of T cells remains
an enigma. It is clear from the data obtained from
the recent microarray study that in BALB/c mice,
P. gingivalis suppresses the T-cell response in a
number of ways including down-regulating the
expression of genes which affect the T-cell receptor
CD3 complex, CD2 binding protein 2 and CD8
expression (87). The down-regulation of genes coding
for a number of cytokines and/or cytokine receptors
suggests a swing away from Th1 responses. Although
a concomitant up-regulation of genes encoding Th2
cytokines was not demonstrated, the overwhelming
results of this study demonstrated that down-regulation of both CD4 and CD8 cells could also lead to
suppression of help for the antigen-specific B-cell
response in periodontitis if P. gingivalis was a major
dental plaque constituent. These results have led to

31

Gemmell et al.

the development of the hypothesis that T cells have a

fundamental role in maintaining immune homeostasis in the presence of the plaque biofilm. In this
context it can be seen to be in the best interest of the
biofilm and of the host if a balance can be reached.
The T-cell response can therefore be considered to be
the default response where activation is balanced
with suppression. It is when this balance is disturbed
that disease progression occurs.
This hypothesis is based on findings using a mouse
model of P. gingivalis infection. However, mice do
not develop periodontal disease and the P. gingivalisinduced immune response is a simple response to
one albeit significant periodontopathic bacterium. In
humans, dental plaque is a complex biofilm. Subgingival plaque, which resides in a more protected
location than supragingival plaque, is not subject to
the same degree of intraoral abrasion or salivary host
defense mechanisms and as with biofilms in general,
is very resistant to removal (48). It is becoming clear
that clusters of bacteria occur (215) and each bacterium in the cluster is likely to affect the responses
induced by the others and vice versa. In this respect a
number of animal models have shown modulation of
the immune response by co-immunization with two
periodontal bacteria. Mice infected with P. gingivalis
together with F. nucleatum had significantly larger
skin lesions than those infected with P. gingivalis
alone while active immunization with P. gingivalis
protected against challenge with both organisms (58).
Chen et al. (36) reported that immunization of
A. actinomycetemcomitans together with P. gingivalis
resulted in first- and second-degree lesions compared with first-degree lesions only, which followed
immunization with A. actinomycetemcomitans alone.
The serum anti-P. gingivalis response was higher in
mice injected with both organisms than in mice
injected with only P. gingivalis although this was not
observed with the anti-A. actinomycetemcomitans
antibody response. Another study showed that
although the levels of anti-F. nucleatum antibodies in
mice injected with F. nucleatum followed by P. gingivalis were the same as in mice immunized with
F. nucleatum alone, antibody levels to P. gingivalis
were very low. In contrast, mice injected with
P. gingivalis followed by F. nucleatum produced
equal levels of both anti-P. gingivalis and anti-F.
nucleatum antibodies, although at lower levels than
the other groups immunized with bacteria respectively (83). Furthermore, the inhibition of neutrophil
phagocytosis of immune serum-opsonized P. gingivalis was shown to be modulated by the presence of
anti-F. nucleatum antibodies, while anti-P. gingivalis

32

antibodies induced an inhibitory effect on the phagocytic response to F. nucleatum (85).These studies
highlight the complex often synergistic responses
with co-infection (55), which may have relevance to
the multibacterial infection found in human periodontal disease.
The role of autoimmunity in chronic inflammation
is also of major interest. In this context it can be
postulated that autoimmunity is a critical and
integral part of chronic inflammation in that it
enhances the removal of collagen by enhancing
fibroblast phagocytosis of protease-digested collagen
fragments as well as the removal of destroyed or
dying cells. Control of this process by regulatory T
cells then becomes fundamental and again if there
is a disturbance in this homeostatic mechanism
enhanced tissue destruction could result.

References
1. Allison JP. CD28B7 interactions in T-cell activation. Curr
Opin Immunol 1994: 6: 414419.
2. Amanuma R, Nakajima T, Yoshie H, Yamazaki K.
Increased infiltration of CD1d+ and natural killer T cells
in periodontal disease tissues. J Periodontal Res 2006: 41:
7379.
3. Amendt C, Mann A, Schirmacher P, Blessing M. Resistance
of keratinocytes to TGFbeta-mediated growth restriction
and apoptosis induction accelerates re-epithelialization in
skin wounds. J Cell Sci 2002: 115: 21892198.
4. Anderson DM, Maraskovsky E, Billingsley WL, Dougall
WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF,
Cosman D, Galibert L. A homologue of the TNF receptor
and its ligand enhance T-cell growth and dendritic-cell
function. Nature 1997: 390: 175179.
5. Aoyagi T, Sugawara-Aoyagi M, Yamazaki K, Hara K.
Interleukin 4 (IL-4) and IL-6-producing memory T-cells in
peripheral blood and gingival tissues in periodontitis
patients with high serum antibody titers to Porphyromonas gingivalis. Oral Microbiol Immunol 1995: 10: 304
310.
6. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy
review of a new approach. Pharmacol Rev 2003: 55: 241269.
7. Ashkenazi M, White RR, Dennison DK. Neutrophil
modulation by Actinobacillus actinomycetemcomitans. II.
Phagocytosis and development of respiratory burst.
J Periodontal Res 1992: 27: 457465.
8. Ashkenazi M, White RR, Dennison DK. Neutrophil
modulation by Actinobacillus actinomycetemcomitans. I.
Chemotaxis, surface receptor expression and F-actin
polymerization. J Periodontal Res 1992: 27: 264273.
9. Attstrom R, Schroeder HE. Effect of experimental neutropenia on initial gingivitis in dogs. Scand J Dent Res
1979: 87: 723.
10. Aviles Mendoza GJ, Seidel NE, Otsu M, Anderson SM,
Simon Stoos K, Herrera A, Hoogstraten Miller S, Malech
HL, Candotti F, Puck JM, Bodine DM. Comparison of five
retrovirus vectors containing the human IL-2 receptor

The role of T cells in periodontal disease

11.

12.
13.

14.

15.

16.

17.
18.

19.

20.

21.

22.
23.

24.

25.

26.
27.

28.

gamma chain gene for their ability to restore T and B

lymphocytes in the X-linked severe combined immunodeficiency mouse model. Mol Ther 2001: 3: 565573.
Azuma M, Yssel H, Phillips JH, Spits H, Lanier LL. Functional expression of B7/BB1 on activated T lymphocytes.
J Exp Med 1993: 177: 845850.
Baker PJ, Roopenian DC. Genetic susceptibility to chronic
periodontal disease. Microbes Infect 2002: 4: 11571167.
Baker PJ, Wilson ME. Opsonic IgG antibody against
Actinobacillus actinomycetemcomitans in localized juvenile periodontitis. Oral Microbiol Immunol 1989: 4: 98105.
Baker PJ, Garneau J, Howe L, Roopenian DC. T-cell
contributions to alveolar bone loss in response to oral
infection with Porphyromonas gingivalis. Acta Odontol
Scand 2001: 59: 222225.
Baranowska HI, Palmer RM, Wilson RF. A comparison of
antibody levels to Bacteroides gingivalis in serum and
crevicular fluid from patients with untreated periodontitis.
Oral Microbiol Immunol 1989: 4: 173175.
Bartova J, Kratka Opatrna Z, Prochazkova J, Krejsa O,
Duskova J, Mrklas L, Tlaskalova H, Cukrowska B. T helper
type 1 and Th2 cytokine profile in patients with early onset
periodontitis and their healthy siblings. Mediators
Inflamm 2000: 9: 115120.
Bendelac A. Mouse NK1+ T cells. Curr Opin Immunol
1995: 7: 367374.
Bendelac A, Hunziker RD, Lantz O. Increased interleukin 4
and immunoglobulin E production in transgenic mice
overexpressing NK1 T cells. J Exp Med 1996: 184: 1285
1293.
Berglundh T, Liljenberg B, Lindhe J. Some cytokine profiles of T-helper cells in lesions of advanced periodontitis.
J Clin Periodontol 2002: 29: 705709.
Bick PH, Carpenter AB, Holdeman LV, Miller GA, Ranney
RR, Palcanis KG, Tew JG. Polyclonal B-cell activation
induced by extracts of Gram-negative bacteria isolated from
periodontally diseased sites. Infect Immun 1981: 34: 4349.
Bleijs DA, de Waal Malefyt R, Figdor CG, van Kooyk Y.
Co-stimulation of T cells results in distinct IL-10 and TNFalpha cytokine profiles dependent on binding to ICAM-1,
ICAM-2 or ICAM-3. Eur J Immunol 1999: 29: 22482258.
Bloom BR, Salgame P, Diamond B. Revisiting and revising
suppressor T cells. Immunol Today 1992: 13: 131136.
Bocko D, Frydecka I. Struktura i funkcja kompleksu TCR/
CD3 limfocytu T. [Structure and function of lymphocyte
TCR/CD3 complex]. Postepy Hig Med Dosw 2003: 57: 519
529.
Born TL, Thomassen E, Bird TA, Sims JE. Cloning of a
novel receptor subunit, AcPL, required for interleukin-18
signaling. J Biol Chem 1998: 273: 944529450.
Boyatzis S, Seymour GJ. Effect of age and periodontal
disease status in man on the spontaneous proliferation of
peripheral blood lymphocytes. Arch Oral Biol 1986: 31:
749755.
Brandtzaeg P, Kraus FW. Autoimmunity and periodontal
disease. Odontol Tidskr 1965: 73: 285393.
Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB.
Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 2003: 4:
12301237.
Bulut Y, Faure E, Thomas L, Equils O, Arditi M. Cooperation of Toll-like receptor 2 and 6 for cellular activation by

29.

30.

31.

32.

33.
34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

soluble tuberculosis factor and Borrelia burgdorferi outer

surface protein A lipoprotein: role of Toll-interacting
protein and IL-1 receptor signaling molecules in Toll-like
receptor 2 signaling. J Immunol 2001: 167: 987994.
Califano JV, Schenkein HA, Tew JG. Immunodominant
antigens of Actinobacillus actinomycetemcomitans serotypes a and c in high-responder patients. Oral Microbiol
Immunol 1991: 6: 228235.
Califano JV, Schenkein HA, Tew JG. Immunodominant
antigens of Actinobacillus actinomycetemcomitans serotype b in early-onset periodontitis patients. Oral Microbiol
Immunol 1992: 7: 6570.
Campbell PA. Editorial Review. The neutrophil, a professional killer of bacteria may be controlled by T cells. Clin
Exp Immunol 1990: 79: 141143.
Carpenter AB, Sully EC, Ranney RR, Bick PH. T-cell regulation of polyclonal B cell activation induced by extracts of
oral bacteria associated with periodontal diseases. Infect
Immun 1984: 43: 326336.
Centrella M, McCarthy TL, Canalis E. Skeletal tissue and
transforming growth factor b. FASEB J 1988: 2: 30663073.
Champaiboon C, Yongvanitchit K, Pichyangkul S,
Mahanonda R. The immune modulation of B-cell
responses by Porphyromonas gingivalis and interleukin10. J Periodontol: 2000: 71: 468475.
Chapple CC, Srivastava M, Hunter N. Failure of macrophage activation in destructive periodontal disease.
J Pathol 1998: 186: 281286.
Chen PB, Davern LB, Katz J, Eldridge JH, Michalek SM.
Host responses induced by co-infection with Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans in a murine model. Oral Microbiol Immunol 1996: 11:
274281.
Chirmule N, Kalyanaraman VS, Slade H, Oyaizu N, Pahwa
S. Requirement of the T cell receptor for antigen presentation by T lymphocytes. Effect of envelope glycoproteins
of HIV-1 on antigen presentation by T cells. Clin Exp
Immunol 1990: 80: 161166.
Cole KC, Seymour GJ, Powell RN. The autologous mixed
lymphocyte reactions (AMLR) using periodontal lymphocytes. J Dent Res 1986: 65: 473 (abstract no. 16).
Cole KC, Seymour GJ, Powell RN. Phenotypic and functional analysis of T cells extracted from chronically
inflamed human periodontal tissues. J Periodontol 1987:
58: 569573.
Collins RA, Werling D, Duggan SE, Bland AP, Parsons KR,
Howard CJ. Gammadelta T cells present antigen to CD4+
alphabeta T cells. J Leukoc Biol 1998: 63: 707714.
Cullinan MP, Westerman B, Hamlet SM, Palmer JE, Faddy
MJ, Lang NP, Seymour GJ. A longitudinal study of interleukin-1 gene polymorphisms and periodontal disease in a
general adult population. J Clin Periodontol 2001: 28:
11371144.
Cullinan MP, Hamlet SM, Westerman B, Palmer JE, Faddy
MJ, Seymour GJ. Acquisition and loss of Porphyromons
gingivalis, Actinobacillus actinomycetemcomitans and
Prevotella intermedia over a 5-year period: the effect of a
triclosan/copolymer dentifrice. J Clin Periodontol 2003:
30: 532541.
Curtis MA, Slaney JM, Carman RJ, Johnson NW. Identification of the major surface protein antigens of Porphyromonas gingivalis using IgG antibody reactivity of

33

Gemmell et al.

44.

45.

46.

47.

48.
49.

50.

51.

52.
53.

54.

55.

56.

57.

58.

59.

34

periodontal casecontrol serum. Oral Microbiol Immunol

1991: 6: 321326.
Cutler SM, Garcia AJ. Engineering cell adhesive surfaces
that direct integrin alpha5beta1 binding using a recombinant fragment of fibronectin. Biomaterials 2003: 24:
17591770.
Cutler CW, Arnold RR, Schenkein HA. Inhibition of C3 and
IgG proteolysis enhances phagocytosis of Porphyromonas
gingivalis. J Immunol 1993: 151: 70167029.
Czuprynski CJ, Henson PM, Campbell PA. Enhanced
accumulation of inflammatory neutrophils and macrophages mediated by transfer of T cells from mice
immunized with Listeria monocytogenes. J Immunol 1985:
134: 34493454.
Darveau RP, Cunningham MD, Bailey T, Seachord C,
Ratcliffe K, Bainbridge B, Dietsch M, Page RC, Aruffo A.
Ability of bacteria associated with chronic inflammatory
disease to stimulate E-selectin expression and promote
neutrophil adhesion. Infect Immun 1995: 63: 13111317.
Darveau RP, Tanner A, Page RC. The microbial challenge
in periodontitis. Periodontol 2000 1997: 14: 1232.
Del Prete G, De Carli M, Almerigogna F, Giudizi MG,
Biagiotti R, Romagnani S. Human IL-10 is produced by both
type 1 helper (T helper type 1) and type 2 helper (Th2) T cell
clones and inhibits their antigen-specific proliferation and
cytokine production. J Immunol 1993: 150: 353360.
Devine L, Sun J, Barr MR, Kavathas PB. Orientation of the
Ig domains of CD8 alpha beta relative to major histocompatibility complex class I. J Immunol 1999: 162: 846851.
Devine L, Kieffer LJ, Aitken V, Kavathas PB. Human CD8
beta, but not mouse CD8 beta, can be expressed in the
absence of CD8 alpha as a beta homodimer. J Immunol
2000: 164: 833838.
Dinarello CA. The biology of interleukin 1 and comparison
to tumor necrosis factor. Immunol Lett 1987: 16: 227232.
Donaldson SL, Ranney RR, Burmeister JA, Tew JG. Blastogenic responses by lymphocytes from periodontally
healthy populations induced by periodontitis-associated
bacteria. J Periodontol 1982: 53: 743751.
Ebersole JL, Taubman MA. The protective nature of host
responses in periodontal diseases. Periodontol 2000 1994:
5: 112141.
Ebersole JL, Brunsvold M, Steffensen B, Wood R, Holt SC.
Effects of immunization with Porphyromonas gingivalis
and Prevotella intermedia on progression of ligatureinduced periodontitis in the nonhuman primate Macaca
fascicularis. Infect Immun 1991: 59: 33513359.
Ebersole JL, Cappelli D, Sandoval MN. Subgingival distribution of A. actinomycetemcomitans in periodontitis.
J Clin Periodontol 1994: 21: 6575.
Ebersole JL, Cappelli D, Sandoval MN, Steffen MJ. Antigen
specificity of serum antibody in A. actinomycetemcomitans-infected periodontitis patients. J Dent Res 1995: 74:
658666.
Ebersole JL, Feuille F, Kesavalu L, Holt SC. Host modulation of tissue destruction caused by periodontopathogens:
effects on a mixed microbial infection composed of Porphyromonas gingivalis and Fusobacterium nucleatum.
Microb Pathog 1997: 23: 2332.
Ebert EC, Mehta V, Das KM. Activation antigens on
colonic T cells in inflammatory bowel disease: effects of
IL-10. Clin Exp Immunol 2005: 140: 157165.

60. Emingil G, Karaarslan F, Keskinoglu A, Coker I, Atilla G.

Phenotypic and functional analysis of peripheral blood
mononuclear cells in generalised aggressive and chronic
periodontitis patients. J Int Acad Periodontol 2001: 3: 8794.
61. Eng HL, Wang CH, Chen CH, Chou MH, Cheng CT, Lin
TM. A CD14 promoter polymorphism is associated with
CD14 expression and Chuman leukocyte antigen mydiastimulated TNF alpha production. Genes Immun 2004: 5:
426430.
62. Engstrom PE, Larsson A, Norhagen G, Smith CI, Sallberg
M, Helgeland K, Hammarstom L. Specificity and levels of
oral and systemic antibodies to Actinobacillus actinomycetemcomitans. J Clin Periodontol 1993: 20: 746751.
63. Engstrom PE, George M, Larsson P, Lally ET, Taichman
NS, Norhagen G. Oral and systemic immunoglobulin
G-subclass antibodies to Actinobacillus actinomycetemcomitans leukotoxin. Oral Microbiol Immunol 1999: 14:
104108.
64. Fives-Taylor P, Meyer D, Mintz K. Characteristics of
Actinobacillus actinomycetemcomitans invasion of and
adhesion to cultured epithelial cells. Adv Dent Res 1995: 9:
5562.
65. Fokkema SJ, Loos BG, Slegte C, van der Velden U. A type 2
response in lipopolysaccharide (LPS)-stimulated whole
blood cell cultures from periodontitis patients. Clin Exp
Immunol 2002: 127: 374378.
66. Ford PJ, Gemmell E, Walker PJ, West MJ, Cullinan MP,
Seymour GJ. Characterization of heat shock protein-specific T cells in atherosclerosis. Clin Diag Lab Immunol
2005: 12: 259267.
67. Fujihashi K, Kono Y, Yamamoto M, McGhee JR, Beagley K,
Aicher WK, Kiyono H. Interleukin production by gingival
mononuclear cells isolated from adult periodontitis
patients. Dent Res 1991: 70: 550 (abstract no. 2269).
68. Fujihashi K, Yamamoto M, McGhee JR, Kiyono H. Type 1/
type 2 cytokine production by CD4+ T cells in adult periodontitis. J Dent Res 1994: 73: 204 (abstract no. 818).
69. Garlet GP, Martins W Jr, Ferreira BR, Milanezi CM, Silva JS.
Patterns of chemokines and chemokine receptors
expression in different forms of human periodontal disease. J Periodontal Res 2003: 38: 210217.
70. Gause WC, Halvorson MJ, Lu P, Greenwald R, Linsley P,
Urban JF, Finkelman FD. The function of costimulatory
molecules and the development of IL-4-producing T cells.
Immunol Today 1997: 18: 115120.
71. Gemmell E, Seymour GJ. Interleukin 1, interleukin 6 and
transforming growth factor-b production by human gingival mononuclear cells following stimulation with Porphyromonas gingivalis and Fusobacterium nucleatum.
J Periodontal Res 1992: 28: 122129.
72. Gemmell E, Seymour GJ. Cytokines and T cell switching.
Crit Rev Oral Biol Med 1994: 5: 249279.
73. Gemmell E, Seymour GJ. Cytokine profiles of cells
extracted from human periodontal diseases. J Dent Res
1998: 77: 1626.
74. Gemmell E, Sved AM, Seymour GJ. Cellular adhesion
molecules on periodontal lymphocytes. Aust Dent J 1995:
40: 129134.
75. Gemmell E, Bird PS, Bowman JD, Xu L, Polak B, Walsh LJ,
Seymour GJ. Immunohistological study of Porphyromonas
gingivalis-induced lesions in a murine model. Oral
Microbiol Immunol 1997: 12: 288297.

The role of T cells in periodontal disease

76. Gemmell E, Marshall RI, Seymour GJ. Cytokines and
prostaglandins in immune homeostasis and tissue
destruction in periodontal disease. Periodontol 2000 1997:
14: 112143.
77. Gemmell E, Winning A, Bird PS, Seymour GJ. Cytokine
profiles of lesional and splenic T cells in Porphyromonas
gingivalis infection in a murine model. J Periodontol 1998:
69: 11311138.
78. Gemmell E, Grieco DA, Seymour GJ. The proportion of
IL-4, IFN-gamma and IL-10 positive cells in P. gingivalis-specific T cell lines established from P. gingivalispositive subjects. Oral Microbiol Immunol 1999: 14:
267274.
79. Gemmell E, Grieco DA, Seymour GJ. Chemokine expression in Porphyromonas gingivalis-specific T cell lines. Oral
Microbiol Immunol 2000: 15: 166171.
80. Gemmell E, Carter CL, Seymour GJ. Chemokines in
human periodontal disease tissues. Clin Exp Immunol
2001: 125: 134141.
81. Gemmell E, McHugh GB, Grieco DA, Seymour GJ.
Costimulatory molecules in human periodontal disease
tissues. J Periodontal Res 2001: 36: 92100.
82. Gemmell E, Carter CL, Hart DNJ, Drysdale KE, Seymour
GJ. Antigen presenting cells in human periodontal disease
tissues. Oral Microbiol Immunol 2002: 17: 388393.
83. Gemmell E, Bird PS, Carter CL, Drysdale KE, Seymour GJ.
Effect of Fusobacterium nucleatum on the T and B cell
responses to Porphyromonas gingivalis in a mouse model.
Clin Exp Immunol 2002: 128: 238244.
84. Gemmell E, Carter CL, Bird PS, Seymour GJ. Genetic
dependence of the specific T cell cytokine response to
P. gingivalis in mice. J Periodontol 2002: 73: 591596.
85. Gemmell E, Bird PS, Ford PJ, Ashman RB, Gosling P, Hu Y,
Seymour GJ. Modulation of the antibody response by
Porphyromonas gingivalis and Fusobacterium nucleatum
in a mouse model. Oral Microbiol Immunol 2004: 19: 247
251.
86. Gemmell E, Carter CL, Seymour GJ. Mast cells in human
periodontal disease. J Dent Res 2004: 83: 384387.
87. Gemmell E, Drysdale KE, Seymour GJ. Gene expression in
splenic CD4 and CD8 cells from BALB/c mice immunized
with Porphyromonas gingivalis. J Periodontol 2006: 77:
622633.
88. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T
cells leads to spontaneous T cell differentiation and
autoimmune disease. Immunity 2000: 12: 171181.
89. Gosling PT, Gemmell E, Carter CL, Bird PS, Seymour GJ.
Immunohistological analysis of Tannerella forsythiainduced lesions in a murine model. Oral Microbiol
Immunol 2005: 20: 2530.
90. Gracie JA, Robertson SE, McInnes IB. Interleukin-18.
J Leukoc Biol 2003: 73: 213224.
91. Gurses N, Unlu F, Hekimgil M, Keskinoglu A. Immunohistochemical characterization of lymphocyte subsets in
chronic adult periodontitis. J Nihon Univ Sch Dent 1996:
38: 94101.
92. Hakamada-Taguchi R, Kato T, Ushijima H, Murakami M,
Uede T, Nariuchi H. Expression and co-stimulatory function of B7-2 on murine CD4+ T cells. Eur J Immunol 1998:
28: 865873.
93. Hart TC. Genetic considerations of risk in human periodontal disease. Curr Opin Periodontol 1994: 311.

94. Hayakawa H, Yamashita K, Ohwaki K, Sawa M, Noguchi T,

Iwata K, Hayakawa T. Collagenase activity and tissue
inhibitor of metalloproteinases-1 (TIMP-1) content in
human whole saliva from clinically healthy and periodontally diseased subjects. J Periodontal Res 1994: 29: 305
308.
95. Hayes SM, Shores EW, Love PE. An architectural perspective on signaling by the pre-, alphabeta and gammadelta T cell receptors. Immunol Rev 2003: 191: 2837.
96. Hemmerle J, Frank RM. Bacterial invasion of periodontal
tissues after experimental immunosuppression in rats.
J Biol Buccale 1991: 19: 271282.
97. Hillmann G, Krause S, Ozdemir A, Dogan S, Geurtsen W.
Immunohistological and morphometric analysis of
inflammatory cells in rapidly progressive periodontitis and
adult periodontitis. Clin Oral Investig 2001: 5: 227235.
98. Hirokawa M, Kitabayashi A, Kuroki J, Miura AB. Signal
transduction by B7/BB1 expressed on activated T lymphocytes: cross-linking of B7/BB1 induces protein tyrosine
phosphorylation and synergizes with signalling through
T-cell receptor/CD3. Immunology 1995: 86: 155161.
99. Hirsch HZ, Tarkowski A, Miller EJ, Gay S, Koopman WJ,
Mestecky J. Autoimmunity to collagen in adult periodontal
disease. J Oral Pathol 1988: 17: 456459.
100. Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs
BL, Khosla S. Interleukin-1beta and tumor necrosis factoralpha, but not interleukin-6, stimulate osteoprotegerin
ligand gene expression in human osteoblastic cells. Bone
1999: 25: 255259.
101. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ,
Riggs BL. The roles of osteoprotegerin and osteoprotegerin
ligand in the paracrine regulation of bone resorption.
J Bone Miner Res 2000: 15: 212.
102. Hong S, Scherer DC, Singh N, Mendiratta SK, Serizawa I,
Koezuka Y, Van Kaer L. Lipid antigen presentation in the
immune system: lessons learned from CD1d knockout
mice. Immunol Rev 1999: 169: 3144.
103. Howard M, OGarra A. Biological properties of interleukin
10. Immunol Today 1992: 13: 198200.
104. Ito H, Harada Y, Matsuo T, Ebisu S, Okada H. Possible role
of T cells in the establishment of IgG plasma cell-rich
periodontal lesion augmentation of IgG synthesis in the
polyclonal B cell activation response by autoreactive T
cells. J Periodontal Res 1988: 23: 3945.
105. Ito H, Honda T, Domon H, Oda T, Okui T, Amanuma R,
Nakajima T, Yamazaki K. Gene expression analysis of the
CD4+ T-cell clones derived from gingival tissues of periodontitis patients. Oral Microbiol Immunol 2005: 20: 382
386.
106. Ivanyi L, Lehner T. Stimulation of lymphocyte transformation by bacterial antigens in patients with periodontal
disease. Arch Oral Biol 1970: 15: 10891096.
107. Jenkins MK, Johnson JG. Molecules involved in T-cell
costimulation. Curr Opin Immunol 1993: 5: 361367.
108. Johnson RB, Serio FG. Interleukin-18 concentrations and
the pathogenesis of periodontal disease. J Periodontol
2005: 76: 785790.
109. Jotwani R, Cutler CW. Multiple dendritic cell (DC) subpopulations in human gingiva and association of mature
DCs with CD4+ T-cells in situ. J Dent Res 2003: 82: 736741.
110. Joyce S, Woods AS, Yewdell JW, Bennink JR, De-Silva AD,
Boesteanu A, Balk SP, Cotter RJ, Brutkiewicz RR. Natural

35

Gemmell et al.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

36

ligand of mouse CD1d1: cellular glycosylphosphatidylinositol. Science 1998: 279: 15411544.

June CH, Bluestone JA, Nadler LM, Thompson CB. The B7
and CD28 receptor families. Immunol Today 1994: 15:
321331.
Kaminski DA, Letterio JJ, Burrows PD. Differential regulation of mouse B cell development by transforming
growth factor beta1. Dev Immunol 2002: 9: 8595.
Karatzas S, Novak MJ, Blieden TM. Cytokine production
by Porphyromonas gingivalis-specific human T cells.
J Dent Res 1996: 75: 322 (abstract no. 2435).
Kelly MN, Kolls JK, Happel K, Schwartzman JD,
Schwarzenberger P, Combe C, Moretto M, Khan IA.
Interleukin-17/interleukin-17 receptor-mediated signaling
is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection.
Infect Immun 2005: 73: 617621.
Kenny E, Mason D, Saoudi A, Pombo A, Ramirez F. CD8
alpha is an activation marker for a subset of peripheral
CD4 T cells. Eur J Immunol 2004: 34: 12621271.
Kimura S, Fugimoto N, Okada H. Impaired autologous
mixed-lymphocyte reaction of peripheral blood lymphocytes in adult periodontitis. Infect Immun 1992: 59: 4418
4424.
Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami
M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K,
Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ,
Suda T. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the
ODF/RANKL-RANK interaction. J Exp Med 2000: 191:
275286.
Kobayashi-Sakamoto M, Isogai E, Hirose K. Porphyromonas gingivalis modulates the production of interleukin
8 and monocyte chemotactic protein 1 in human vascular
endothelial cells. Curr Microbiol 2003: 46: 109114.
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli
C, Morony S, Oliveira dos Santos AJ, Van G, Itie A, Khoo W,
Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ,
Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node
organogenesis. Nature 1999: 397: 315323.
Kornman KS, Crane A, Wang HY, di Giovine FS, Newman
MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW.
The interleukin-1 genotype as a severity factor in adult
periodontal disease. J Clin Periodontol 1997: 24: 7277.
Korostoff JM, Wang JF, Sarment DP, Stewart JC, Feldman
RS, Billings PC. Analysis of in situ protease activity in
chronic adult periodontitis patients: expression of activated MMP-2 and a 40 kDa serine protease. J Periodontol
2000: 71: 353360.
Kovats S, Grubin CE, Eastman S, deRoos P, Dongre A, Van
Kaer L, Rudensky AY. Invariant chain-independent function of H-2M in the formation of endogenous peptidemajor histocompatibility complex class II complexes in
vivo. J Exp Med 1998: 187: 245251.
Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW,
Legaspi A, Liu PT, Cole ST, Godowski PJ, Maeda Y, Sarno
EN, Norgard MV, Brennan PJ, Akira S, Rea TH, Modlin RL.
Activation and regulation of Toll-like receptors 2 and 1 in
human leprosy. Nat Med 2003: 9: 525532.
Kurihara H, Nishimura F, Nakamura T, Nakagawa M,
Tanimoto I, Nomura Y, Kokeguchi S, Kato K, Murayama Y.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

Humoral immune response to an antigen from Porphyromonas gingivalis 381 in periodontal disease. Infect
Immun 1991: 59: 27582762.
Lamont RJ, Jenkinson HF. Life below the gum line:
pathogenic mechanisms of Porphyromonas gingivalis.
Microbiol Mol Biol Rev 1998: 62: 12441263.
Lappin DF, MacLeod CP, Kerr A, Mitchell T, Kinane DF.
Anti-inflammatory cytokine IL-10 and T cell cytokine
profile in periodontitis granulation tissue. Clin Exp
Immunol 2001: 123: 294300.
Lee WI, Zhu Q, Gambineri E, Jin Y, Welcher AA, Ochs HD.
Inducible CO-stimulator molecule, a candidate gene for
defective isotype switching, is normal in patients with
hyper-IgM syndrome of unknown molecular diagnosis.
J Allergy Clin Immunol 2003: 112: 958964.
Lindhe J, Liljenberg B, Listgarten M. Some microbiological
and histopathological features of periodontal disease in
man. J Periodontol 1980: 51: 264269.
Ling TY, Sims TJ, Chen HA, Whitney CW, Moncla BJ, Engel
LD, Page RC. Titer and subclass distribution of serum IgG
antibody reactive with Actinobacillus actinomycetemcomitans in localized juvenile periodontitis. J Clin Immunol
1993: 13: 101112.
Liu D, Xu JK, Figliomeni L, Huang L, Pavlos NJ, Rogers M,
Tan A, Price P, Zheng MH. Expression of RANKL and OPG
mRNA in periodontal disease: possible involvement in
bone destruction. Int J Mol Med 2003: 11: 1721.
Lopatin DE, Blackburn E. Avidity and titer of immunoglobulin G subclasses to Porphyromonas gingivalis in
adult periodontitis patients. Oral Microbiol Immunol
1992: 7: 332337.
Lorenzo J. Interactions between immune and bone cells:
new insights with many remaining questions. J Clin Invest
2000: 106: 749752.
Lourbakos A, Chinni C, Thompson P, Potempa J, Travis J,
Mackie EJ, Pike RN. Cleavage and activation of proteinaseactivated receptor-2 on human neutrophils by gingipain-R
from Porphyromonas gingivalis. FEBS Lett 1998: 435:
4548.
Lu B, Ebensperger C, Dembic Z, Wang Y, Kvatyuk M, Lu T,
Coffman RL, Pestka S, Rothman PB. Targeted disruption of
the interferon-gamma receptor 2 gene results in severe
immune defects in mice. Proc Natl Acad Sci U S A 1998: 95:
82338238.
Lundqvist CA, Taubman MA, Stoufi ED, Liu XP, Smith DJ.
Diminished immunoglobulin synthesis after stimulation
of mononuclear cells from periodontal disease tissue. Reg
Immunol 1992: 4: 255261.
Lye E, Mirtsos C, Suzuki N, Suzuki S, Yeh WC. The role of
interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase
activity in IRAK-4-mediated signaling. J Biol Chem 2004:
279: 4065340658.
Mackler BF, Frostad KB, Robertson PB, Levy BM. Immunoglobulin bearing lymphocytes and plasma cells in
human periodontal disease. J Periodontal Res 1977: 12:
3745.
Madianos PN, Papapanou PN, Sandros J. Porphyromonas
gingivalis infection of oral epithelium inhibits neutrophil
transepithelial migration. Infect Immun 1997: 65: 3983
3990.
Mahanonda R, Sa Ard Iam N, Yongvanitchit K, Wisetchang
M, Ishikawa I, Nagasawa T, Walsh DS, Pichyangkul S.

The role of T cells in periodontal disease

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

Upregulation of co-stimulatory molecule expression and

dendritic cell marker (CD83) on B cells in periodontal
disease. J Periodontal Res 2002: 37: 177183.
Makela M, Salo T, Uitto VJ, Larjava H. Matrix metalloproteinases (MMP-2 and MMP-9) of the oral cavity: cellular origin and relationship to periodontal status. J Dent
Res 1994: 73: 13971406.
Mangan DF, Won T, Lopatin DE. Nonspecific induction of
immunoglobulin M antibodies to periodontal diseaseassociated microorganisms after polyclonal human
B-lymphocyte activation by Fusobacterium nucleatum.
Infect Immun 1983: 41: 10381045.
Mangan DF, Taichman NS, Lally ET, Wahl SM. Lethal
effects of Actinobacillus actinomycetemcomitans leukotoxin on human T lymphocytes. Infect Immun 1991: 59:
32673272.
Manhart SS, Reinhardt RA, Payne JB, Seymour GJ,
Gemmell E, Dyer JK, Petro TM. Gingival cell IL-2 and IL-4
in early-onset periodontitis. J Periodontol 1994: 65: 807
813.
Mathur P, Murray B, Crowell T, Gardner H, Allaire N, Hsu
YM, Thill G, Carulli JP. Murine peptidoglycan recognition
proteins PglyrpIalpha and PglyrpIbeta are encoded in the
epidermal differentiation complex and are expressed in
epidermal and hematopoietic tissues. Genomics 2004: 83:
11511163.
Matsuyama T, Kawai T, Izumi Y, Taubman MA. Expression
of MHC class II and CD80 by gingival epithelial cells
induces activation of CD4+ T cells in response to bacterial
challenge. Infect Immun 2005: 73: 10441051.
Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd,
Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K,
Schneewind O, Walker D, Beutler B, Teyton L, Savage PB,
Bendelac A. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 2005: 434: 525529.
Meghji S, Henderson B, Kirby A, Newman HN, Wilson M.
Serum antibody response to surface-associated material
from periodontopathogenic bacteria. FEMS Immunol Med
Microbiol 1995: 10: 101108.
Meikle MC, Hembry RM, Holley J, Horton C, McFarlane
CG, Reynolds JJ. Immunolocalization of matrix metalloproteinases and TIMP-1 (tissue inhibitor of metalloproteinases) in human gingival tissues from periodontitis
patients. J Periodontal Res 1994: 29: 118126.
Michalowicz BS. Genetic and heritable risk factors in
periodontal disease. J Periodontol 1994: 65(Suppl. 5): 479
488.
Mieza MA, Itoh T, Cui JQ, Makino Y, Kawano T, Tsuchida
K, Koike T, Shirai T, Yagita H, Matsuzawa A, Koseki H,
Taniguchi M. Selective reduction of V alpha 14+ NK T cells
associated with disease development in autoimmuneprone mice. J Immunol 1996: 156: 40354040.
Milla C, Yang S, Cornfield DN, Brennan ML, Hazen SL,
Panoskaltsis Mortari A, Blazar BR, Haddad IY. Myeloperoxidase deficiency enhances inflammation after allogeneic
marrow transplantation. Am J Physiol Lung Cell Mol
Physiol 2004: 287: L706L714.
Mogi M, Otogoto J, Ota N, Togari A. Differential expression
of RANKL and osteoprotegerin in gingival crevicular fluid
of patients with periodontitis. J Dent Res 2004: 83: 166
169.

153. Mooney J, Kinane DF. Humoral immune responses to

Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans in adult periodontitis and rapidly progressive
periodontitis. Oral Microbiol Immunol 1994: 9: 321326.
154. Mooney J, Adonogianaki E, Kinane DF. Relative avidity of
serum antibodies to putative periodontopathogens in
periodontal disease. J Periodontal Res 1993: 28: 444450.
155. Musgrave BL, Watson CL, Hoskin DW. CD2CD48 interactions promote cytotoxic T lymphocyte induction and
function: anti-CD2 and anti-CD48 antibodies impair
cytokine synthesis, proliferation, target recognition/
adhesion, and cytotoxicity. J Interferon Cytokine Res 2003:
23: 6781.
156. Nagasawa T, Kobayashi H, Kiji M, Aramaki M, Mahanonda
R, Kojima T, Murakami Y, Saito M, Morotome Y, Ishikawa
I. LPS-stimulated human gingival fibroblasts inhibit the
differentiation of monocytes into osteoclasts through the
production of osteoprotegerin. Clin Exp Immunol 2002:
130: 338344.
157. Nakagawa S, Machida Y, Nakagawa T, Fujii H, Yamada S,
Takazoe I, Okuda K. Infection by Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, and
antibody responses at different ages in humans. Periodontal Res 1994: 29: 916.
158. Nakajima T, Yamazaki K, Cullinan MP, Gemmell E, Seymour GJ. T-cell antigen specificity in humans following
stimulation with Porphyromonas gingivalis. Arch Oral Biol
1999: 44: 10451053.
159. Nakajima T, Ueki-Maruyama K, Oda T, Ohsawa Y, Ito H,
Seymour GJ, Yamazaki K. Regulatory T-cells infiltrate
periodontal disease tissues. J Dent Res 2005: 84: 639643.
160. Nakamori M, Iwahashi M, Nakamura M, Ueda K, Zhang X,
Yamaue H. Intensification of antitumor effect by T helper
1-dominant adoptive immunogene therapy for advanced
orthotopic colon cancer. Clin Cancer Res 2003: 9: 2357
2365.
161. Nakayama K, Kawachi Y, Tokito S, Minami N, Yamamoto
R, Imai T, Gachelin G, Nakauchi H. Recent duplication of
the two human CD8 beta-chain genes. J Immunol 1992:
148: 19191927.
162. Nambiar MP, Fisher CU, Warke VG, Krishnan S, Mitchell
JP, Delaney N, Tsokos GC. Reconstitution of deficient T
cell receptor zeta chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus.
Arthritis Rheum 2003: 48: 19481955.
163. Nishizawa K, Freund C, Li J, Wagner G, Reinherz EL.
Identification of a proline-binding motif regulating CD2triggered T lymphocyte activation. Proc Natl Acad Sci U S
A 1998: 95: 1489714902.
164. OGarra A. Peptide regulatory factors. Interleukins and the
immune system 1. Lancet 1989: 1: 943946.
165. Oda T, Yoshie H, Yamazaki K. Porphyromonas gingivalis
antigen preferentially stimulates T cells to express IL-17
but not receptor activator of NF-jB ligand in vitro. Oral
Microbiol Immunol 2003: 18: 3036.
166. Offenbacher S. Periodontal diseases: pathogenesis. Ann
Periodontol 1996: 1: 821878.
167. Ohno H, Nakamura T, Yagita H, Okumura K, Taniguchi M,
Saito T. Induction of negative signal through CD2 during
antigen-specific T cell activation. J Immunol 1991: 147:
21002106.

37

Gemmell et al.
168. Okada H, Murakami S. Cytokine expression in periodontal
health and disease. Crit Rev Oral Biol Med 1998: 9: 248266.
169. Okada H, Ito H, Harada Y. T-cell requirement for establishment of the IgG-dominant B-cell lesion in periodontitis. J Periodontal Res 1987: 22: 187189.
170. Okada H, Shimabukuro Y, Kassai Y, Ito H, Matsuo T, Ebisu
S, Harada Y. The function of gingival lymphocytes on the
establishment of human periodontitis. Adv Dent Res 1988:
2: 364367.
171. Page RC, Schroeder HE. Pathogenesis of inflammatory
periodontal disease. A summary of current work. Lab
Invest 1976: 34: 235249.
172. Page RC, Offenbacher S, Schroeder HE, Seymour GJ,
Kornman KS. Advances in the pathogenesis of periodontitis: summary of developments, clinical implication and
future directions. Periodontol 2000 1997: 14: 216248.
173. Perraudeau M, Taylor PR, Stauss HJ, Lindstedt R, Bygrave
AE, Pappin DJ, Ellmerich S, Whitten A, Rahman D, Canas
B, Walport MJ, Botto M, Altmann DM. Altered MHC class
II peptide loading in H2-O-deficient mice. Eur J Immunol
2000: 30: 28712880.
174. Petit MD, Hovenkamp E, Hamann D, Roos MT, van der
Velden U, Miedema F, Loos BG. Phenotypical and functional analysis of T cells in periodontitis. J Periodontal Res
2001: 36: 214220.
175. Pilon M, Williams-Miller C, Cox DS. Interleukin-2 levels in
gingival crevicular fluid in periodontitis. J Dent Res 1991:
70: 550 (abstract no. 2270).
176. Polak B, Vance JB, Dyer JK, Bird PS, Gemmell E, Reinhardt
RA, Seymour GJ. IgG antibody subclass response to
Porphyromonas gingivalis outer membrane antigens in
gingivitis and adult periodontitis. J Periodontol 1995: 66:
63368.
177. Porcelli S, Yockey CE, Brenner MB, Balk SP. Analysis of T
cell antigen receptor (TCR) expression by human peripheral blood CD4-8-alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR
alpha chain. J Exp Med 1993: 178: 116.
178. Poulter LW, Seymour GJ, Duke O, Janossy G, Panayi G.
Immunohistological analysis of delayed-type hypersensitivity in man. Cell Immunol 1982: 74: 358369.
179. Prabhu A, Michalowicz BS, Mathur A. Detection of local
and systemic cytokines in adult periodontitis. J Periodontol 1996: 67: 515522.
180. Qwarnstrom EE, MacFarlane SA, Page RC. Effects of
interleukin-1 on fibroblast extracellular matrix, using a
3-dimensional culture system. J Cell Physiol 1989: 139:
501508.
181. Reinhardt RA, Bolton RW, McDonald TL, Dubois LM,
Kaldahl WB. In situ lymphocyte subpopulations from
active versus stable periodontal sites. J Periodontol 1988:
59: 656670.
182. Reinhardt RA, McDonald TL, Bolton RW, Dubois LM,
Kaldahl WB. IgG subclasses in gingival crevicular fluid
from active versus stable periodontal sites. J Periodontol
1989: 60: 4450.
183. Reinherz EL. A molecular basis for thymic selection:
regulation of T11 induced thymocyte expansion by the
T3-Ti antigen/MHC receptor pathway. Immunol Today
1985: 6: 7579.
184. Reinherz EL, Schlossman SF. The differentiation and
function of human T lymphocytes. Cell 1980: 19: 821827.

38

185. Reynolds JJ, Meikle MC. Mechanisms of connective tissue

matrix destruction in periodontitis. Periodontol 2000 1997:
14: 144157.
186. Romagnani S. Human T HELPER TYPE 1 and TH2 subsets:
regulation of differentiation and role in protection and
immunopathology. Int Arch Allergy Immunol 1992: 98:
279285.
187. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002: 39: 279291.
188. Ryder MI, Hyun W, Loomer P, Haqq C. Alteration of gene
expression profiles of peripheral mononuclear blood cells
by tobacco smoke: implications for periodontal diseases.
Oral Microbiol Immunol 2004: 19: 3949.
189. Saglie FR, Marfany A, Camargo P. Intragingival occurrence
of Actinobacillus actinomycetemcomitans and Bacteroides
gingivalis in active destructive periodontal lesions. J Periodontol 1988: 59: 259265.
190. Saito A, Hosaka Y, Nakagawa T, Seida K, Yamada S,
Takazoe I, Okuda K. Significance of serum antibody
against surface antigens of Actinobacillus actinomycetemcomitans in patients with adult periodontitis. Oral
Microbiol Immunol 1993: 8: 146153.
191. Salvi GE, Brown CE, Fujihashi K, Kiyono H, Smith FW,
Beck JD, Offenbacher S. Inflammatory mediators of the
terminal dentition in adult and early onset periodontitis.
J Periodontal Res 1998: 33: 212225.
192. Sandros J, Papapanou P, Dahlen G. Porphyromonas gingivalis invades oral epithelial cells in vitro. J Periodontal
Res 1993: 28: 219226.
193. Schenkein HA. The effect of periodontal proteolytic Bacteroides species on proteins of the human complement
system. J Periodontal Res 1988: 23: 187192.
194. Schenkein HA, Fletcher HM, Bodnar M, Macrina FL.
Increased opsonization of a prtH-defective mutant of
Porphyromonas gingivalis W83 is caused by reduced
degradation of complement-derived opsonins. J Immunol
1995: 154: 53315337.
195. Seguier S, Gogly B, Bodineau A, Godeau G, Brousse N. Is
collagen breakdown during periodontitis linked to
inflammatory cells and expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases
in human gingival tissue? J Periodontol 2001: 72: 1398
1406.
196. Sester DP, Beasley SJ, Sweet MJ, Fowles LF, Cronau SL,
Stacey KJ, Hume DA. Bacterial/CpG DNA down-modulates colony stimulating factor-1 receptor surface expression on murine bone marrow-derived macrophages with
concomitant growth arrest and factor-independent survival. J Immunol 1999: 163: 65416550.
197. Seymour GJ. Possible mechanisms involved in the
immunoregulation of chronic inflammatory periodontal
disease. J Dent Res 1987: 66: 29.
198. Seymour GJ, Greenspan JS. The phenotypic characterization of lymphocyte subpopulations in established human
periodontal disease. J Periodontal Res 1979: 14: 3946.
199. Seymour GJ, Taylor JJ. Shouts and whispers: an introduction to immunoregulation in periodontal disease.
Periodontol 2000 2004: 35: 913.
200. Seymour GJ, Powell RN, Davies WI. Conversion of a stable
T-cell lesion to a progressive B-cell lesion in the pathogenesis of chronic inflammatory periodontal disease: an
hypothesis. J Clin Periodontol 1979: 6: 267277.

The role of T cells in periodontal disease

201. Seymour GJ, Powell RN, Davies WIR. The immunopathogenesis of chronic inflammatory periodontal disease.
J Oral Pathol 1979: 8: 249265.
202. Seymour GJ, Powell RN, Aitken JF. Experimental gingivitis
in humans: a clinical and histological investigation.
J Periodontol 1983: 54: 522528.
203. Seymour GJ, Cole KL, Powell RN, Lewins E, Cripps AW,
Clancy RL. Interleukin-2 production and bone resorption
activity by unstimulated lymphocytes extracted from
chronically inflamed human periodontal tissues. Arch
Oral Biol 1985: 30: 481484.
204. Seymour GJ, Gemmell E, Walsh LJ, Powell RN. Immunohistological analysis of experimental gingivitis in humans.
Clin Exp Immunol 1988: 71: 132137.
205. Shenker BJ, Datar S. Fusobacterium nucleatum inhibits
human T-cell activation by arresting cells in the mid-G1
phase of the cell cycle. Infect Immun 1995: 63: 48304836.
206. Shenker BJ, Slots J. Immunomodulatory effects of Bacteroides products on in vitro human lymphocyte functions.
Oral Microbiol Immunol 1989: 4: 2429.
207. Shenker BJ, McArthur WP, Tsai CC. Immune suppression
induced by Actinobacillus actinomycetemcomitans. I.
Effects on human peripheral blood lymphocyte responses
to mitogens and antigens. J Immunol 1982: 128: 148154.
208. Shenker BJ, Vitale L, Slots J. Immunosuppressive effects of
Prevotella intermedia on in vitro human lymphocyte
activation. Infect Immun 1991: 59: 45834589.
209. Sigusch B, Klinger G, Glockmann E, Simon HU. Earlyonset and adult periodontitis associated with abnormal
cytokine production by activated T lymphocytes. J Periodontol 1998: 69: 10981104.
210. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS,
Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T,
Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL,
Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L,
Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ.
Osteoprotegerin: a novel secreted protein involved in the
regulation of bone density. Cell 1997: 89: 309319.
211. Singh N, Hong S, Scherer DC, Serizawa I, Burdin N, Kronenberg M, Koezuka Y, Van Kaer L. Cutting edge: activation of NK T cells by CD1d and alpha-galactosylceramide
directs conventional T cells to the acquisition of a Th2
phenotype. J Immunol 1999: 163: 23732377.
212. Slots J. Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in periodontal disease: introduction. Periodontol 2000 1999: 20: 713.
213. Slots J. Herpesviruses in periodontal diseases. Periodontol
2000 2005: 38: 3362.
214. Smith PC, Munoz VC, Collados L, Oyarzun AD. In situ
detection of matrix metalloproteinase-9 (MMP-9) in gingival epithelium in human periodontal disease. J Periodontal Res 2004; 39: 8792.
215. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL
Jr. Microbial complexes in subgingival plaque. J Clin
Periodontol 1998: 25: 134144.
216. Socransky SS, Haffajee AD, Smith C, Duff GW. Microbiological parameters associated with IL-1 gene polymorphisms in periodontitis patients. J Clin Periodontol 2000:
27: 810818.
217. Spitzer JH, Visintin A, Mazzoni A, Kennedy MN, Segal DM.
Toll-like receptor 1 inhibits Toll-like receptor 4 signaling
in endothelial cells. Eur J Immunol 2002: 32: 11821187.

218. Stashenko P, Resmini LM, Haffajee AD, Socransky SS. T

cell responses of periodontal disease patients and healthy
subjects to oral microorganisms. J Periodontal Res 1983:
18: 587600.
219. Stashenko P, Dewhirst FE, Peros WJ, Kent RL, Ago JM.
Synergistic interactions between interleukin 1, tumor
necrosis factor, and lymphotoxin in bone resorption.
J Immunol 1987: 138: 14641468.
220. Stoufi ED, Taubman MA, Ebersole JL, Smith DJ, Stashenko
PP. Phenotypic analyses of mononuclear cells recovered
from healthy and diseased human periodontal tissues.
J Clin Immunol 1987: 235245.
221. Sundqvist GK, Carlsson J, Herrmann BF, Hofling JF,
Vaatainen A. Degradation in vivo of the C3 protein of
guinea-pig complement by a pathogenic strain of Bacteroides gingivalis. Scand J Dent Res 1984: 92: 1424.
222. Suzuki JB, Martin SA, Vincent JW, Falkler WA Jr. Local and
systemic production of immunoglobulins to periodontopathogens in periodontal disease. J Periodontal Res 1984:
19: 599603.
223. Suzuki N, Chen NJ, Millar DG, Suzuki S, Horacek T, Hara
H, Bouchard D, Nakanishi K, Penninger JM, Ohashi PS,
Yeh WC. IL-1 receptor-associated kinase 4 is essential for
IL-18-mediated NK and T helper type 1 cell responses.
J Immunol 2003: 170: 40314035.
224. Szalay G, Ladel CH, Blum C, Brossay L, Kronenberg M,
Kaufmann SH. Cutting edge: anti-CD1 monoclonal antibody treatment reverses the production patterns of TGFbeta 2 and T helper type 1 cytokines and ameliorates
listeriosis in mice. J Immunol 1999: 162: 69556958.
225. Tabeta K, Yamazaki K, Hotokezaka H, Yoshie H, Hara K.
Elevated humoral immune response to heat shock protein
60 family in periodontitis patients. Clin Exp Immunol
2000: 120: 285293.
226. Tacchini-Cottier F, Mayer WE, Begovich AB, Jones PP.
Inactivation of E alpha and E beta expression in inbred
and wild mice by multiple distinct mutations, some of
which predate speciation within Mus species. Int Immunol 1995: 7: 14591471.
227. Taichman NS, Dean RT, Sanderson CJ. Biochemical and
morphological characterization of the killing of human
monocytes by a leukotoxin derived from Actinobacillus
actinomycetemcomitans. Infect Immun 1980: 28: 258268.
228. Taichman NS, Iwase M, Lally ET, Shattil SJ, Cunningham
ME, Korchak HM. Early changes in cytosolic calcium and
membrane potential induced by Actinobacillus actinomycetemcomitans leukotoxin in susceptible and resistant
target cells. J Immunol 1991: 147: 35873594.
229. Takahashi N, Udagawa N, Suda T. A new member of
tumor necrosis factor ligand family, ODF/OPGL/TRANCE/
RANKL, regulates osteoclast differentiation and function.
Biochem Biophys Res Commun 1999: 256: 449455.
230. Takamatsu HH, Denyer MS, Wileman TE. A sub-population of circulating porcine gammadelta T cells can act as
professional antigen presenting cells. Vet Immunol
Immunopathol 2002: 87: 223224.
231. Takeda K, Dennert G. The development of autoimmunity
in C57BL/6 lpr mice correlates with the disappearance of
natural killer type 1-positive cells: evidence for their suppressive action on bone marrow stem cell proliferation, B
cell immunoglobulin secretion, and autoimmune symptoms. J Exp Med 1993: 177: 155164.

39

Gemmell et al.
232. Takeichi O, Haber J, Kawai T, Smith DJ, Moro I, Taubman
MA. Cytokine profiles of T-lymphocytes from gingival
tissues with pathological pocketing. J Dent Res 2000: 79:
15481555.
233. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K,
Dong Z, Modlin RL, Akira S. Cutting edge: role of Toll-like
receptor 1 in mediating immune response to microbial
lipoproteins. J Immunol 2002: 169: 1014.
234. Taubman MA, Stoufi ED, Ebersole JL, Smith DJ. Phenotypic studies of cells from periodontal disease tissue.
J Periodontal Res 1984: 19: 587590.
235. Taylor PA, Lees CJ, Fournier S, Allison JP, Sharpe AH,
Blazar BR. B7 expression on T cells down-regulates
immune responses through CTLA-4 ligation via TT
interactions [corrections]. J Immunol 2004: 172: 3439.
236. Teng YT. The role of acquired immunity and periodontal
disease progression. Crit Rev Oral Biol Med 2003: 14: 237
252.
237. Teng YT, Nguyen H, Gao X, Kong YY, Gorczynski RM,
Singh B, Ellen RP, Penninger JM. Functional human T-cell
immunity and osteoprotegerin ligand control alveolar
bone destruction in periodontal infection. J Clin Invest
2000; 106: R59R67.
238. Tew J, Engel D, Mangan D. Polyclonal B-cell activation in
periodontitis. J Periodontal Res 1989: 24: 225241.
239. Tiranathanagul S, Pattamapun K, Yongchaitrakul T, Pavasant P. MMP-2 activation by Actinobacillus actinomycetemcomitans supernatant in human PDL cells was corresponded
with reduction of TIMP-2. Oral Dis 2004: 10: 383388.
240. Tokoro Y, Matsuki Y, Yamamoto T, Suzuki T, Hara K. Relevance of local Th2-type cytokine mRNA expression in
immunocompetent infiltrates in inflamed gingival tissue to
periodontal diseases. Clin Exp Immunol 1997: 107: 166174.
241. Undale AH, van den Elsen PJ, Celis E. Antigen-independent acquisition of MHC class II molecules by human T
lymphocytes. Int Immunol 2004: 16: 15231533.
242. Underwood K, Sjostrom K, Darveau R, Lamont R,
Schenkein H, Gunsolley J, Page R, Engel D. Serum antibody opsonic activity against Actinobacillus actinomycetemcomitans in human periodontal diseases. J Infect Dis
1993: 168: 14361443.
243. Van Houten N, Mixter PF, Wolfe J, Budd RC. CD2
expression on murine intestinal intraepithelial lymphocytes is bimodal and defines proliferative capacity. Int
Immunol 1993: 5: 665672.
244. Vernal R, Chaparro A, Graumann R, Puente J, Valenzuela
MA, Gamonal J. Levels of cytokine receptor activator of
nuclear factor kappaB ligand in gingival crevicular fluid in
untreated chronic periodontitis patients. J Periodontol
2004: 75: 15861591.
245. Villela B, Cogen RB, Bartolucci AA, Birkedal-Hansen H.
Crevicular fluid collagenase activity in healthy, gingivitis,
chronic adult periodontitis and localized juvenile periodontitis patients. J Periodontal Res 1987: 22: 209211.
246. Viville S, Neefjes J, Lotteau V, Dierich A, Lemeur M, Ploegh
H, Benoist C, Mathis D. Mice lacking the MHC class IIassociated invariant chain. Cell 1993: 72: 635648.
247. Wang QT. The distribution and significance of collagen
type III and fibronectin in human gingiva. Zhonghua Kou
Qiang Yi Xue Za Zhi 1992: 27: 336338, 384.
248. Wassenaar A, Reinhardus C, Thepen T, Abraham Inpijn L,
Kievits F. Cloning, characterization, and antigen specific-

40

249.

250.

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

ity of T-lymphocyte subsets extracted from gingival tissue

of chronic adult periodontitis patients. Infect Immun 1995:
63: 21472153.
Wassenaar A, Reinhardus C, Abraham Inpijn L, Kievits F.
Type-1 and type-2 CD8+ T-cell subsets isolated from chronic
adult periodontitis tissue differ in surface phenotype and
biological functions. Immunology 1996: 87: 113118.
Westerlund U, Ingman T, Lukinmaa PL, Salo T, Kjeldsen L,
Borregaard N, Tjaderhane L, Konttinen YT, Sorsa T.
Human neutrophil gelatinase and associated lipocalin in
adult and localized juvenile periodontitis. J Dent Res 1996:
75: 15531563.
Whitney C, Ant J, Moncla B, Johnson B, Page RC, Engel D.
Serum immunoglobulin G antibody to Porphyromonas gingivalis in rapidly progressive periodontitis: titer, avidity, and
subclass distribution. Infect Immun 1992: 60: 21942200.
Wilhelmsen K, Burkhalter S, van der Geer P. C-Cbl binds
the CSF-1 receptor at tyrosine 973, a novel phosphorylation site in the receptors carboxy-terminus. Oncogene
2002: 21: 10791089.
Wilkins AL, Yang W, Yang JJ. Structural biology of the cell
adhesion protein CD2: from molecular recognition to
protein folding and design. Curr Protein Pept Sci 2003: 4:
367373.
Wilton JM, Hurst TJ, Sterne JA. Elevated opsonic activity
for Porphyromonas (Bacteroides) gingivalis in serum from
patients with a history of destructive periodontal disease.
A casecontrol study. J Clin Periodontol 1993: 20: 563569.
Wynne SE, Walsh LJ, Seymour GJ, Powell RN. In situ
demonstration of Natural Killer (NK) cells in human gingival tissue. J Periodontol 1986: 57: 699702.
Wyss Coray T, Mauri Hellweg D, Baumann K, Bettens F,
Grunow R, Pichler WJ. The B7 adhesion molecule is
expressed on activated human T cells: functional
involvement in TT cell interactions. Eur J Immunol 1993:
23: 21752180.
Yamamoto M, Fujihashi K, Hiroi T, McGhee JR, Van Dyke
TE, Kiyono H. Molecular and cellular mechanisms for
periodontal diseases: role of T helper type 1 and Th2 type
cytokines in induction of mucosal inflammation. J Periodontal Res 1997: 32: 115119.
Yamazaki K, Ohsawa Y, Yoshie H. Elevated proportion of
natural killer T cells in periodontitis lesions: a common
feature of chronic inflammatory diseases. Am J Pathol
2001: 158: 13911398.
Yamazaki K, Ohsawa Y, Tabeta K, Ito H, Ueki K, Oda T,
Yoshie H, Seymour GJ. Accumulation of human heat
shock protein 60-reactive T cells in the gingival tissues of
periodontitis patients. Infect Immun 2002: 70: 24922501.
Yoshioka M, Yokoyama N, Masuda K, Honna T, Hinode D,
Nakamura R, Rouabhia M, Mayrand D, Grenier D. Effect of
hydroxamic acid-based matrix metalloproteinase inhibitors on human gingival cells and Porphyromonas gingivalis. J Periodontol 2003: 74: 12191224.
Yun PL, Decarlo AA, Collyer C, Hunter N. Hydrolysis of
interleukin-12 by Porphyromonas gingivalis major cysteine
proteinases may affect local gamma interferon accumulation and the T helper type 1 or Th2 T-cell phenotype in
periodontitis. Infect Immun 2001: 69: 56505660.
Zhang JH, Ferrante A, Arrigo AP, Dayer JM. Neutrophil
stimulation and priming by direct contact with activated
human T lymphocytes. J Immunol 1992: 148: 177181.