molecular oral
microbiology
molecular oral microbiology
T cells, teeth and tissue destruction – what do
T cells do in periodontal disease?
L. Campbell1, E. Millhouse2, J. Malcolm1 and S. Culshaw1,2
1 Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
2 Infection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences,
University of Glasgow, Glasgow, UK
Correspondence: Shauna Culshaw, Infection and Immunity Research Group, Glasgow Dental School of Medicine, College of Medical,
Veterinary and Life Sciences, University of Glasgow, 378 Sauchiehall Street, Glasgow G2 3JZ, UK Tel.: +44 (0)141 211 9739;
E-mail: shauna.culshaw@glasgow.ac.uk
Keywords: adaptive immunity; animal model; human; periodontitis
Accepted 22 October 2015
DOI: 10.1111/omi.12144
SUMMARY
The microbial plaque biofilm resides adjacent to
the tissue-destructive inflammatory infiltrate in
periodontitis. Although not sufficient, this biofilm
is necessary for this inflammatory response.
Patients with periodontitis generate antibodies
specific for bacteria in the biofilm – although the
role of these antibodies is not clear, there is,
undoubtedly, an adaptive immune response in
periodontitis. T lymphocytes are central to adaptive
immunity, and provide help for B cells to generate
specific antibodies. T-cell receptor recognition of
peptide antigen in the context of major histocom-
patibility complex can result in T-cell activation.
The activation and differentiation of the T-cell can
take many forms, and hence numerous types of T
cells have been described. The role of adaptive
immune responses, and the T-cell component
thereof, in periodontitis remains relatively poorly
defined. This review aims to broadly summarize
findings about T cells and their role in periodonti-
tis, focusing primarily on studies of human disease
with a short discussion of some animal studies.
INTRODUCTION
Periodontitis is a chronic inflammatory disease, which
causes loss of alveolar bone and ultimately results in
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Molecular Oral Microbiology 31 (2016) 445–456
REVIEW
tooth loss. It is the most common cause of bone loss
in humans, with almost 50% of the adult population in
the UK being affected, rising to 60% of those aged
65 and over (Petersen et al., 2005; Chapple, 2014).
Treatment for the disease and resulting tooth loss is
costly, time consuming, and requires meticulous, life-
long supportive care. Moreover, the inflammation in
the oral cavity may have systemic consequences and
impact on diabetes (Casanova et al., 2014), cardio-
vascular disease risk (Dietrich et al., 2013) and
rheumatoid arthritis (Kaur et al., 2013). Hence, there
is a need for a better understanding of the systemic
implications of this inflammation in the oral cavity,
and for novel treatment and prevention strategies for
periodontitis.
Dental plaque is necessary but not sufficient for
periodontitis (Loe et al., 1986). The magnitude of tis-
sue destruction in response to the biofilm is deter-
mined largely by the host response, with genetics
(Michalowicz et al., 1991), smoking (Ismail et al.,
1983) and diet (Bawadi et al., 2011) all influencing an
individual’s susceptibility to periodontitis.
The components of immune dysregulation in peri-
odontitis may be viewed in several ways:
• as an exaggerated or inappropriate inflammatory
response to microbial challenge;
• as a failure to resolve inflammation;
445

T cells in the pathogenesis of periodontitis
• as an autoimmune response;
• or as a combination of all of these.
This review seeks to address how CD4 T cells may
influence these possible pathways of immune dysreg-
ulation. T cells play key roles in several inflamma-
tory diseases, exemplified by the prominence of
T-cell-associated genes identified in genome-wide
association studies of rheumatoid arthritis and
Crohn’s disease (The Welcome Trust Case Control
Consortium, 2007) and the success of some T-cell
targeting therapies such as Abatacept in rheumatoid
arthritis (Gizinski & Fox, 2014). T lymphocytes
express a T-cell receptor (TCR) for the recognition of
specific peptide antigen within the major histocompat-
ibility complex (MHC) binding groove (Fig. 1). Esti-
mates suggest that about 1 : 100,000 T cells will
recognize any given foreign antigen – and that T-cell
cross-reactivity with more than one peptide–MHC
complex is essential (Mason, 1998). Hence, antigen-
specific cells are rare, approximately 100 out of the
total naive T-cell pool are likely to recognize a pep-
tide–MHC complex (Jenkins & Moon, 2012; Tubo
et al., 2013). Once they have found their cognate
antigen, the local microenvironment dictates what
happens next. CD4 helper and regulatory T (Treg)
cells express a wide array of different cell surface
molecules (Fig. 1) and secrete a myriad of cytokines
to instruct the immune response; it is these CD4 cells
that are the focus of this narrative.
CD4 T CELLS IN PERIODONTITIS
The role of T cells in human periodontitis has proved
difficult to definitively dissect. Studies of periodontal
health in human immunodeficiency virus (HIV)-posi-
tive patients suggest an association with CD4 count
and age, and that pharmacological control of HIV,
which protects the CD4 cell counts, may abrogate
impact on the periodontium. Compared with HIV-sero-
negative controls, HIV-seropositive patients are more
frequently diagnosed with necrotizing periodontitis
(Ryder et al., 2012). Pharmacological immune sup-
pression is relatively commonly used to treat autoim-
munity and prevent transplant rejection. The immune
suppressive treatment cyclosporin A, inhibits cal-
cineurin and prevents translocation of the cytosolic
component of nuclear factor of activated T cells,
thereby blocking the production of interleukin-4 (IL-4),
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L. Campbell et al.
Figure 1 T-cell surface molecules. T cells communicate with other
cells and their environment through a coordinated network of sur-
face ligand/receptor interactions on the cell surface, which direct the
subsequent immune responses. T cells interact with antigen-pre-
senting cells through the T-cell receptor (TCR) comprised of an
a- and b-chain, each with a variable (v) and constant (c) region,
along with dimeric signaling molecules CD3de and CD3ce. The
interaction with the antigen-presenting cells is enhanced through the
co-receptors CD4/CD8 for MHC class II/I respectively. The TCR
complex confers the antigen specificity of the T-cell response. Fur-
ther instructions that dictate the nature of that response come from
co-stimulatory receptors such as CD27, CD28, CD40 ligand
(CD40L), or co-inhibitory receptors including cytotoxic T lymphocyte
antigen 4 (CTLA4), programmed cell death protein (PD1), and
CD28 inducible co-stimulator (ICOS). Activation of T cells causes
gene upregulation and production of cytokines via nuclear factor-jB
(NF-jB) and mitogen-activated protein kinase (MAPK), including
interleukin-2 (IL-2) protein release, which promotes T-cell activation
and survival through binding via IL-2 receptor (IL-2R) in a positive
feedback loop.
IL-2 and CD40 ligand (CD40L) (Ho et al., 1996).
Transplant patients receiving cyclosporin A treatment
frequently suffer gingival overgrowth, but this broad
inhibition of T-cell activation does not seem to cause
rapid progression of periodontal disease (Pejcic et al.,
2014). This negligible impact on periodontal bone
loss following treatment with cyclosporin A was mir-
rored in animal studies (da Silva Peralta et al., 2015).
Overall, human conditions of T-cell deficiency have
shed little light on their role in periodontitis. Genome-
wide association studies of patients with periodontitis
have suggested associations with genes involved in
immune function (Divaris et al., 2013), but by compar-
ison with diseases such as rheumatoid arthritis the
associations are relatively weak. Class II MHC poly-
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L. Campbell et al. T cells in the pathogenesis of periodontitis

morphisms can point to a role for T cells in disease T HELPER CELLS – TH1 AND TH2
susceptibility. In rheumatoid arthritis, human leukocyte
The characterization of activated CD4 T cells accord-
antigen (HLA) Class II discrepancies account for 30–
ing to their cytokine production and function (Fig. 2)
50% of the genetic susceptibility to rheumatoid arthri-
initially described two distinct cytokine profiles and
tis (Raychaudhuri et al., 2012). This is not so clear in
functions (Mosmann et al., 1986). This dogma of a
periodontitis. Meta-analysis of HLA associations in
dichotomous T-cell response was applied to numer-
periodontitis revealed no association with variations in
ous diseases, and their pathology was described as
MHC Class II (Stein et al., 2008). In spite of such
being either T helper type 1 (Th1) or Th2 associated.
apparently weak evidence of a role for T cells in peri-
Th1 cells are associated with protection against intra-
odontitis, numerous investigators have demonstrated
cellular pathogens and cancerous cells, whereas Th2
changes in T cells in periodontitis.

Figure 2 T-cell subsets. Stimulation of naive CD4+ T-cells with cognate antigen in the context of MHC Class II, along with co-stimulatory sig-
nals from the antigen-presenting cells, and specific combinations of cytokines, will result in differentiation into T-cell subsets each with differ-
ent functions. These can be characterized by their transcription factors (as labeled inside each cell) and cytokine release (labeled in the
green box). Other cytokines can inhibit differentiation into each subset (red box). The function of each subset has been studied- some subsets
in greater detail than others. In broad terms, T helper type 1 (Th1) and Th2 cells combat intracellular and extracellular pathogens respectively.
Th17 cells can promote inflammation at mucosal sites such as the gingival margin. T follicular helper (Tfh) cells provide B-cell help in the
lymph nodes. Regulatory T cells, both inducible (iTreg) and effector (effector Treg) regulate inflammatory immune responses. Abbreviations:
GATA3, GATA-binding factor 3; 2AHR, 2 aryl hydrocarbon receptor; RORct, retinoid-related orphan receptor-ct; BCL6, B-cell lymphoma 6;
Foxp3, forkhead box protein 3; TGF-b, transforming growth factor-b; IFN-c, interferon-c; RANKL, receptor activator of nuclear factor-jB ligand.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 447
Molecular Oral Microbiology 31 (2016) 445–456

T cells in the pathogenesis of periodontitis
cells are associated with immunity to extracellular
pathogens and humoral immunity. Rheumatoid arthri-
tis, type 1 diabetes and multiple sclerosis were
described as Th1 diseases; allergy and asthma were
designated Th2-driven diseases (Kidd, 2003). Studies
of human periodontal tissues suggested that the ratio
of Th1 to Th2 cells in gingival tissue contributes to
the development and pathogenesis of periodontitis.
Th1 cytokines were found in almost all periodontitis
gingival tissues and were therefore associated with a
susceptible individual, whereas Th2 cytokines were
found less frequently (Seymour et al., 1993). The T
cells in diseased gingival tissues were reported to
predominantly express the chemokine receptors
CCR5 and CXCR3, which are characteristic of Th1
cells (Gamonal et al., 2001; Taubman & Kawai,
2001). Ligands for these receptors, CCL5 and
CXCL10, were elevated in diseased tissues. There
were conflicting studies demonstrating that unstimu-
lated cells isolated from patients with early-onset peri-
odontitis (Manhart et al., 1994) or advanced
periodontitis produced predominantly Th2 cytokines
(Lappin et al., 2001). Furthermore, CD4 T cells iso-
lated from inflamed gingival tissues of patients with
periodontitis expressed both Th1 and Th2 cytokines,
supporting the concept of a co-existence of Th1 and
Th2 cells in periodontitis (Takeichi et al., 2000; Ber-
glundh et al., 2002). Subsequently, novel cytokines
that could not be attributed to these T helper subsets
were discovered, and new T-cell subsets emerged.
TH17 CELLS
The discovery of Th17 cells stemmed from the obser-
vation that IL-23-deficient mice are highly resistant to
experimental autoimmune encephalitis. In this sys-
tem, experimental autoimmune encephalitis was the
result of IL-23 driving the development of a patho-
genic T-cell population characterized by their expres-
sion of IL-17A, IL-17F and IL-6 – Th17 cells (Langrish
et al., 2005). An explosion of studies of Th17 cells
ensued (Gaffen, 2009; Cheng et al., 2014).
There is elevated expression of mRNA for Th17
inducing cytokines il1b, il6 and il21 in the gingival
tissue of patients with periodontitis compared with the
healthy control tissue (Gaffen & Hajishengallis, 2008;
Cardoso et al., 2009; Dutzan et al., 2012). Inter-
leukin-23p19-producing macrophages have been
detected in severely inflamed lesion sites, which may
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L. Campbell et al.
provide a source of IL-23 to amplify the Th17
response observed in chronic periodontitis (Allam
et al., 2011). Transforming growth factor-b (TGF-b)
was detectable only at lower levels in disease tissues
compared with healthy tissues (Dutzan et al., 2012).
However, TGF-b may be dispensable for Th17 differ-
entiation (Ghoreschi et al., 2010). Numerous studies
have documented elevated expression of IL-17 in
periodontitis tissues compared with healthy controls
(Beklen et al., 2007; Cardoso et al., 2009; Allam
et al., 2011; Adibrad et al., 2012; Awang et al., 2014)
and patients with gingivitis (Honda et al., 2008; Mout-
sopoulos et al., 2012). This IL-17 is generally
reported to be expressed by T cells (Cardoso et al.,
2009) but has also been found in mast cells (our
unpublished observations; Culshaw et al., 2011). The
cytokines necessary for Th17 cell differentiation are
present in the inflamed periodontal tissue but the dri-
ver of these Th17 cells in periodontitis is presumed to
be microbial in origin. Cell culture supernatants from
human antigen-presenting cells stimulated with Por-
phyromonas gingivalis preferentially induced a Th17
response. This biased T-cell differentiation was
assumed to be the result of relatively little IL-12p35,
combined with the greater resistance of IL-1 over IL-
12 to proteolytic degradation by gingipains – hence
creating an environment favoring Th17 development
(Moutsopoulos et al., 2012). In addition to elevated
IL-17A in the gingival crevicular fluid of patients with
periodontitis, elevated levels of IL-35 protein and Ebi3
and Il12A mRNA (components of IL-35) have been
reported. Interleukin-35 is a suppressor of Th17;
therefore it may be increased in periodontitis to com-
pensate for the increased number of Th17 cells
(Mitani et al., 2015). Clearly Th17 cells are present in
periodontitis, but where these cells differentiate and
their function has been difficult to elucidate in human
observational studies (Mitani et al., 2015).
T HELPER CELL PLASTICITY
The variation in T cells identified in different studies of
human tissues likely reflects the challenges of studying
a multifactorial chronic disease. T helper cell plasticity
may further confound these studies. Differentiated T
cells can display different effector phenotypes upon
appropriate restimulation. This phenomenon has been
most studied in Th17 cells, some of which express IL-
12Rb2, and in response to IL-12 can co-express T-bet
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Molecular Oral Microbiology 31 (2016) 445–456

L. Campbell et al.
and convert to non-classic Th1 cells (Nistala et al.,
2010). In juvenile autoimmune arthritis, most IL-17-pro-
ducing cells in synovial fluid show expression of both
the Th17 transcription factor RORC2 and the Th1 tran-
scription factor T bet (Nistala et al., 2010). In Crohn’s
disease patients with fistulating disease, Th1, Th17 and
Th1/17 intermediate cells are found in greater numbers
in the fistula compared with peripheral blood, showing
that these ‘intermediate’ cells are present in inflamma-
tory sites (Maggi et al., 2013). Interleukin-17-producing
‘Th2’ cells have been identified in patients with atopic
asthma in significantly higher frequencies than in
healthy controls. These cells express classical Th2
cytokines (IL-4, IL-5 and IL-13) along with IL-17 and IL-
22, and express transcription factors characteristic of
both subsets of T cells. These Th2/17 cells expressed
CD45RO, CCR4 and CXCR4, suggestive of a memory
phenotype (Wang et al., 2010). T helper cell plasticity
occurs predominantly in sites of inflammation. To the
best of our knowledge, at this time, there is limited evi-
dence of T helper cell plasticity in periodontitis but this
offers one potential explanation for the variable T helper
cell characteristics reported in different studies.
THE INDUCTION AND MAINTENANCE OF T
HELPER SUBSETS
The phenotype of the antigen-presenting cell, and the
local cytokine milieu, instruct initial T-cell differentia-
tion and may subsequently alter the memory T-cell
phenotype and contribute to T-cell plasticity. The local
antigen-presenting cells and the cytokine milieu in
periodontitis have been elegantly reviewed elsewhere
(Cutler & Teng, 2007; Kinane et al., 2011; Preshaw &
Taylor, 2011). The induction of the initial response of
naive T cells to antigen in the gingival tissues may be
assumed to occur in the local draining lymph nodes,
although the kinetics and mechanics – specific to the
oral mucosa – of this initial response are relatively
poorly defined. There are undoubtedly tissue-resident
memory cells within the oral mucosa, although, there
is limited information about whether the memory
T cells are truly tissue resident or are migratory, cen-
tral memory T cells travelling through vessels present
within the tissue. The T cells within the oral mucosa
may exist as intraepithelial lymphocytes (IEL), or in
oral lymphoid foci. Histological studies of gingival
biopsies from healthy controls, gingivitis and peri-
odontitis identified fewer than 20 CD3 cells per mm of
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Molecular Oral Microbiology 31 (2016) 445–456
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T cells in the pathogenesis of periodontitis
epithelium in health and around five-fold increase in
cell numbers in periodontitis. CD8, not CD4, was co-
localized in these studies and these data imply that
the majority of the CD3 cells are CD8, with relatively
few CD4 (Seguier et al., 2000). In both health and
periodontitis, T cells in the oral mucosa are predomi-
nantly CD45RO+ memory phenotype, with a small
proportion of CD45RA+ naive cells. However, in peri-
odontitis, the proportion of CD45RA+ naive T cells, is
greater than in health. Cells obtained from the gingi-
val tissues proliferated following in vitro stimulation
with P. gingivalis, and other bacteria associated with
periodontitis. The proliferative response of the gin-
giva-derived cells was greater than that from matched
peripheral-blood-derived T cells, suggesting that a
number of the gingival T cells are specific for oral
bacteria (Gemmell et al., 1992). Similar findings are
documented in buccal mucosa, in the context of oral
lichen planus; naive CD45RA+ CD4 cells were absent
from control epithelium, but comprised 24% of CD4
cells in oral lichen planus (Walton et al., 1998). These
data suggest that in health IEL are predominantly of
memory phenotype, but in inflammation naive T cells
can populate this niche too.
In addition to IEL, there are reports of oral lymphoid
foci, with areas of CD83 mature dendritic cells local-
ized with CD4 in human periodontitis tissues (Jotwani
et al., 2001). The function of the IEL, and lympho-
cytes in foci, remain relatively poorly defined. The IEL
within the gut are strategically positioned to provide
rapid defense against intestinal pathogens. They can
secrete interferon-c and tumor necrosis factor and
have been shown to migrate to the lamina propria
where it is suggested that the cells modulate the
immune response (Sun et al., 2015).
Myriad factors determine the induction and mainte-
nance of memory cells, and the associated potential
plasticity of the immune response. Compared with a
primary response to pathogens, the recall of memory
shows less stringent requirements for antigen presen-
tation by MHC and co-stimulation. Numerous studies
have demonstrated that IL-7 and IL-15 are required for
the survival and proliferation of memory cells (reviewed
by MacLeod et al., 2010). In gingival tissues, IL-15
abundance exceeds that of IL-2, and this IL-15 may be
key to the proliferation and survival of memory cells, as
has been demonstrated in other sites (Lappin et al.,
2001). Similarly, the signals that maintain the resident
memory cells are unknown. Local antigen-presenting
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T cells in the pathogenesis of periodontitis
cells could reactivate adjacent T cells, and there is also
likely to be bystander cell activation, for example
through the effects of stromal signals.
T CELLS AND OSTEOIMMUNOLOGY
T cells play damaging roles in other bone destructive
disorders such as rheumatoid arthritis. CD4+ T cells
from synovial fluid of patients with rheumatoid arthritis
have been shown to express receptor activator of
nuclear factor jB ligand (RANKL), which directly
induces differentiation of osteoclast progenitor cells
into mature osteoclasts (Kotake et al., 2001).
RANKL is a key cytokine in the bone destruction of
periodontitis. Enzyme-linked immunosorbent assay,
confocal microscopy and RNA detection methods pin-
pointed the primary cellular source of RANKL to Th1
and Th17 type T cells (Kawai et al., 2006; Vernal
et al., 2006; Han et al., 2009, 2013). So it seems likely
that activated T cells may have a direct impact on
bone resorption in inflamed periodontal tissues (Taub-
man & Kawai, 2001; Belibasakis & Bostanci, 2012).
REGULATION OF INFLAMMATION BY T CELLS
Although T cells play roles in the destructive bone
loss observed in periodontitis through RANKL expres-
sion and inflammatory cytokine production,
CD25+ Foxp3+ Treg cells display protective roles
against pathogenic bone resorption through their anti-
inflammatory properties. Treg cells function to down-
regulate Th1 and Th2 immune responses through
their expression of IL-10 and TGF-b (Sakaguchi,
2005). The production of IL-10 by these cells has
been found to inhibit RANKL expression by activated
human peripheral blood T cells in vitro. Moreover,
increasing concentrations of IL-10 in gingival tissue is
associated with decreasing concentrations of soluble
RANKL (Ernst et al., 2007). Flow cytometry analysis
of tissues taken from 10 patients with periodontitis
identified increased numbers of Treg cells,
CD45RO+ CD4+ CD25+ Foxp3+ in the inflammatory
infiltrate of diseased gingival tissues. Some of these
Treg cells expressed TGF-b. In the same study,
immunofluorescence identified CD25+ cells in the
inflammatory infiltrate. The expression of both IL-10
and TGF-b transcripts were increased in periodontitis-
affected tissue (Cardoso et al., 2008). However, an
earlier study identified CD25+ cells in the inflamma-
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L. Campbell et al.
tory infiltrate, but found co-localization of Foxp3 and
CD25 only in healthy tissues and not in periodontal
disease tissues, suggesting a deficiency of Treg cells
in periodontal disease (Ernst et al., 2007). It is cur-
rently impossible to accurately describe the extent of
contribution of Treg cells in human periodontitis.
T-CELL SPECIFICITY IN PERIODONTITIS
The T cell is unique in its expression of the TCR,
which confers its antigen specificity. The majority of T
cells in the inflammatory infiltrate show CD45RO
expression, characteristic of memory T cells (Gem-
mell et al., 1992). There are also some naive T cells
present in the tissue, based on their expression of
CD45RA (Gemmell et al., 1992). The microbial pla-
que biofilm is presumed to be the source of the anti-
gen seen by the CD45RO+ T cells.
Currently, the specificity of the T cells in periodonti-
tis is poorly defined. The TCR repertoire, as
assessed by Vb or Va usage (Fig. 1) in the gingivae
differs from that in the peripheral blood. The predomi-
nance of a particular Vb gene seems to vary between
studies, and on the cell population studied, for exam-
ple CD45RO+ compared with CD45RO cells (Ber-
glundh et al., 1998; Karimzadeh et al., 1999; Gao &
Teng, 2002). The use of MHC tetramers has allowed
identification of antigen-specific T cells in RA (Snir
et al., 2011). This is a challenging technique in multi-
factorial inflammatory human disease, as it requires
identification of peptide antigen and HLA-typing of
patients. To date, tetramers have successfully been
developed to track P. gingivalis-specific memory/ef-
fector T cells in the murine model of periodontitis (Bit-
tner-Eddy et al., 2013). Moreover, there have been
significant recent advances in molecular means of
evaluating T-cell antigen specificity, which allow sin-
gle cell analysis of TCR specificity and transcriptional
profiles (Han et al., 2014). These advances will be
crucial to identifying antigen-specific memory T cells
infiltrating periodontal tissues and elucidating their
effector function. Given the variability in the microbial
biofilm, both between and within patients, there is the
possibility that the clonality of the T cells in the
inflammatory infiltrate changes over time and if so,
this may relate to their function in disease. Overall,
the majority of antibodies in the gingival crevicular
fluid and gingiva of patients with periodontitis are gen-
erally found to belong to the IgG class; IgA is the next
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Molecular Oral Microbiology 31 (2016) 445–456

L. Campbell et al.
most commonly found, and then IgM (Berglundh &
Donati, 2005). Hence there are B cells producing
class-switched antibodies, which presumably have
received T-cell help to generate class switching and
B-cell expansion.
There are a number of studies suggesting an
autoimmune component to periodontitis. Many of
these studies have focused on B-cell components of
an autoimmune response and demonstrated that in
periodontitis, there are elevated titers of autoantibod-
ies recognizing type I collagen, fibronectin and lami-
nin (De-Gennaro et al., 2006). Isotype-switched IgG
anti-collagen antibodies have also been identified in
the gingiva of patients with periodontitis (Anusak-
sathien et al., 1992), and CD5+ B cells isolated from
inflamed gingiva are proficient in producing anti-col-
lagen antibodies of both IgM and IgG classes (Suga-
wara et al., 1992). To date, no autoreactive T cells,
which are required to support B-cell isotype-switching
and affinity-maturation of autoreactive antibodies, in
periodontitis have been identified. However, T-cell-
independent B-cell activation could be induced by sol-
uble factors, including B-cell-activating factor (Gumus
et al., 2014) and the cooperation of epithelium-
derived mediators such as thymic stromal lymphopoi-
etin (Astrakhan et al., 2007). The nature and extent
of any T-cell component of the autoreactive response
in periodontitis remains to be elucidated.
There are limitations in attempting to dissect cell
function in human chronic inflammatory disease; in
patients with periodontitis, for example, it is impossi-
ble to accurately define disease duration and activity.
Animal models allow investigation of known and con-
trollable stages of disease, and manipulation of com-
ponents of the T-cell response.
MURINE STUDIES OF T CELLS IN
PERIODONTITIS
Severe combined immunodeficient mice are unable to
complete V(D)J recombination of gene segments,
causing a lack of productive generation of surface
immunoglobulin on B cells or TCR on T cells resulting
in complete T-cell and B-cell deficiency. Oral infection
of severe combined immunodeficient mice with
P. gingivalis results in less alveolar bone loss than
that observed in similarly infected immunocompetent
mice. Hence, a potentially destructive role for adap-
tive immunity in periodontitis was suggested (Baker
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T cells in the pathogenesis of periodontitis
et al., 1994). Further studies demonstrated deletion of
the a-chain of the TCR to specifically delete T cells
resulted in decreased bone loss (Baker et al., 2002).
CD8+ T-cell and natural killer T-cell knockout mice
showed no significant change in bone loss after oral
infection (Baker et al., 1999). Combined, these results
highlight a role for CD4+ T cells in periodontal dis-
ease, implying a net contribution to bone destruction.
These studies endeavor to give a ‘global’ picture of
T-cell contributions. Many other studies using in vivo
models have sought to look at defined aspects of T-
cell function, in particular the T-cell contribution to the
exaggerated or inappropriate inflammatory response
to microbial challenge.
The Th1/Th2 paradigm has been explored using
gene knockout mice deficient in associated cytokines.
For example, interferon-c knockout mice appeared
protected from bone loss following oral infection with
P. gingivalis (Baker et al., 1999); however, infection
with Aggregatibacter actinomycetemcomitans, was
fatal following disseminated infection and exaggerated
acute-phase response (Garlet et al., 2008). Clearly,
although animal models offer a platform for exploring
and forming hypotheses, it can be difficult to extrapo-
late such findings to human disease, other than to
postulate that interferon-c plays a role both in protec-
tion against periodontal bacterial infections, and in
inflammation-induced tissue damage and bone loss in
periodontitis. Studies of IL-33 in animals suggest that
this Th2 cytokine is likely to promote bone destruction
following infection (Malcolm et al., 2015). Investiga-
tions into the role of Th17 responses in murine models
of periodontitis yielded conflicting results. Mice defi-
cient in IL-17RA show increased bone loss following
oral infection with P. gingivalis. In this model, IL-17-
dependent neutrophil recruitment to infected gingival
tissue was imperative for defense against bacterial
infection. Hence IL-17RA-deficient mice show reduced
recruitment of neutrophils to the inflamed gingival tis-
sue and increased bone loss (Yu et al., 2007). Con-
versely, Del-1-deficient mice revealed a role for IL-17
in promoting bone destruction. Interleukin-17 inhibits
Del-1 expression, thereby promoting neutrophil recruit-
ment; and in this setting the neutrophil recruitment
appears to be more destructive than protective (Eskan
et al., 2012). Neutralizing RANKL with either antibod-
ies or its natural decoy osteoprotegerin, has offered
protection against bone loss induced by oral infection
(Han et al., 2013; Malcolm et al., 2015) and elevated
451

T cells in the pathogenesis of periodontitis
Figure 3 The role of T cells in the immune dysregulation of peri-
odontitis. Bacterial biofilm grows on the surface of the tooth in close
proximity to the gingival epithelial cells of the oral sulcus initiating
the host immune response. T cells can play multiple roles in the
immune dysregulation that contributes to the pathology of periodon-
titis. (i) Exaggerated response to microbial challenge. Activated T
helper type 1 (Th1), Th2 and Th17 cells can produce a variety of
proinflammatory cytokines that can activate immune cells such as
dendritic cells, neutrophils and B cells. Activation of both T cells
and subsequently B cells can cause RANKL production, which
causes alveolar bone destruction by osteoclasts resulting in tooth
loss. (ii) Autoimmunity. The activation of B cells by T follicular helper
cells (Tfh) in either peripheral lymph nodes or tertiary lymph organs
can result in clonal activation of B cells, which produce antibodies
to recognize bacterial components (green antibodies); however, pro-
duction of autoantibodies to collagen, fibronectin and laminin (red
antibodies) can contribute to local destruction of the gingivae. (iii)
Failure to resolve inflammation. Regulatory T (Treg) cells typically
protect against local destruction through their anti-inflammatory
properties. In periodontitis a lack of Treg cells or an inability of
those present to reduce local inflammatory responses by other
immune cells may play a role in the chronic inflammation associated
with periodontitis.
expression of RANKL has been demonstrated in T
cells in these models. However, to date, there are no
reports of specific targeting of T-cell-derived RANKL
in these models. Elegant studies have documented
the role of Treg cells in murine models of periodontitis.
Inhibiting Treg function by targeting glucocorticoid-
inducible tumor necrosis factor receptor (anti-GITR)
exacerbated disease with increased alveolar bone
loss and increased influx of inflammatory cells. Hence,
Treg cells can limit disease without causing immune
suppression sufficient to allow dissemination of bacte-
rial infection (Garlet et al., 2010). Further studies
demonstrated that local administration of C-C motif
chemokine ligand 22 (CCL22) recruited Treg cells to
gingival tissues, decreasing inflammation and reduc-
ing alveolar bone loss (Glowacki et al., 2013). Overall,
these and numerous other animal studies tend to por-
452
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L. Campbell et al.
tray a role for T cells in periodontitis. Nevertheless,
similar to human studies, there are both similarities
and discrepancies in their findings.
CONCLUSIONS
T cells are indisputably present in periodontitis, and the
findings of decades of human and animal studies point
to dynamic and varied functions for these cells (Fig. 3).
The unique feature of T cells is their TCR, and a key
question remains: what is the specificity of T cells at the
initiation of periodontitis and does this change through-
out disease? There have been significant advances in
molecular and cellular techniques for investigating TCR
specificity along with T-cell function. Understanding T
cells better may provide a rationale for investigating
local delivery of T-cell-targeting therapies used in other
inflammatory diseases. More broadly, the relationship
between the adaptive response and the biofilm is lar-
gely unknown. This question is of interest in under-
standing not just periodontitis but almost any other
inflammatory pathology at a mucosal surface.
ACKNOWLEDGEMENTS
LC was supported by a Sir Jules Thorn PhD
Studentship, EM was supported by BBSRC CASE
Studentship, JM was supported by ‘Gums&Joints’
EUFP7 Health (261460), Chief Scientists Office
SDC13, Arthritis Research UK 20823; and SC was
supported by the Scottish Funding Council Scottish
Senior Clinical Fellowship Scheme. The authors
declare no conflict of interest.
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