Available online at www.sciencedirect.
com
Immune responses in the skin in old age
Milica Vukmanovic-Stejic1, Malcolm HA Rustin2, Janko Nikolich-Zugich3
and Arne N Akbar1
A marked increase in the susceptibility to cutaneous infections
and malignancies has been observed in older humans
indicating that cutaneous immunity becomes defective with
age. In this review we will focus on recent developments in the
understanding of age-related changes in immune function of
the skin with a particular emphasis on how alterations in the
interaction between cells involved in innate and adaptive
immunity leads to decreased cutaneous antigen-specific T cell
immunosurveillance.
Addresses
1
Division of Infection and Immunity, Department of Immunology,
University College London, London W1T 4JF, United Kingdom
2
Department of Dermatology, Royal Free Hospital, London NW3 2QG,
United Kingdom
3
Department of Immunobiology and the Arizona Center on Aging,
University of Arizona College of Medicine, Tucson, AZ 85719, USA
Corresponding author: Akbar, Arne N (a.akbar@ucl.ac.uk)
Current Opinion in Immunology 2011, 23:525–531
This review comes from a themed issue on
Immune Senescence
Edited by Beatrix Grubeck-Loebenstein and John Cambier
Available online 22nd June 2011
0952-7915/$ – see front matter
# 2011 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2011.05.008
Skin and immunity
The skin forms the body’s largest interface with the
environment and its principal function is that of a barrier.
It protects the organism by being impermeable to a multi-
tude of harmful exogenous substances and maintains
internal homeostasis by preventing excessive water and
heat loss. In addition there is a highly specialised immune
system consisting of leukocytes that are resident, recruited
or re-circulate within the tissue (Table 1). These cells are
distributed in the epidermal and dermal layers of the skin
and participate in both adaptive and innate immune
responses. They are also responsible for distinguishing
self from non-self which is of fundamental importance
since the skin comes into daily contact with exogenous
substances. Close interlinking between innate and adap-
tive pathways of immunity plays an important role in the
initiation and amplification of immune responses in this
tissue. However, there is a decrease in cutaneous immune
function in older humans that leads to increased bacterial
(such as Streptococus and Staphylococus induced celluli-
tis) and fungal infections (often candidaiasis) [1] and
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contributes to the increase in cutaneous malignancies
[2,3]. This indicates that defective cutaneous immunity
develops during ageing and the purpose of this article to
assess recent data that clarify the nature of the defect
that occurs.
The investigation of antigen-specific T cell
responses in the skin
Since the induction and amplification of cutaneous immu-
nity is an integrated multistep process, in vivo experimen-
tal models are the most informative. A particularly useful
experimental system is the delayed type hypersensitivity
(DTH) response, where recall antigens are injected intra-
dermally [4–6]. This is a classical model of an antigen-
specific memory T cell (secondary) response since indi-
viduals (mice or humans) who have not been exposed to
the antigen do not respond to the antigen challenge [4–7].
The level of DTH reactions in humans is determined by
the diameter of cutaneous induration and the extent of
erythema at the site of antigen injection at 48 h after
antigen injection or in mice by the amount of ear or
footpad swelling at 24 h [4–7]. There are some differ-
ences in the kinetics and nature of the response in mice
and humans, possibly due to the different site of antigen
injection nevertheless, broadly speaking, the cellular
infiltrates are similar in both species [4–7]. While other
experimental models for the study of cutaneous immu-
nity in mice exist [8,9], in humans, the DTH response
provides an ethically acceptable model to study the
kinetics and regulation of a memory T cell response in
vivo. In subsequent sections we will mainly discuss the
human DTH response and how it has been used to study
changes in cutaneous immunity during ageing.
From a histological perspective, antigen exposure and
trauma to the skin induce non-specific danger signals to
recruit and activate cells of the innate immune system
and at very early time points (4–6 h) the majority of
infiltrating cells are neutrophils [5]. This cellular infiltra-
tion is dependent on the production of pro-inflammatory
cytokines such as IFN-g and TNFa that stimulate
expression of adhesion molecules on the endothelium
and increase permeability of the local blood vessel [10].
E-selectin is induced on capillary endothelium as early as
1–2 h after injection and by 12 h adhesion molecules
ICAM-1 and VCAM-1 are also expressed [7]. These
molecules interact with LFA-1 and VLA-4 on monocytes
and lymphocytes allowing the accumulation of these cells
in the dermis [7,11]. In parallel with the endothelial
activation and conditioning at the site of antigen
exposure, antigen presenting cells from the skin transport
Current Opinion in Immunology 2011, 23:525–531
526 Immune Senescence
Table 1
Cells of the adaptive and innate immune system in the skin
Resident
Innate Keratinocytes
Endothelial cells
-Vascular
-Lymphatic
Dendritic cells
Mast cells
Tissue macrophages
Adaptive T lymphocytes
? indicates that there is a possibility, in this case, rather than strong evidence.
antigen to the lymph node where they present it to and
activate memory T cells that subsequently migrate via
blood into the site of inflammation in the skin [10]. The
infiltration of T cells during a DTH response is biphasic,
comprising an early non-specific infiltration of these cells
that appear around dermal blood vessels approximately
12 h after challenge [7] and a later peak of antigen-
specific T cell accumulation [4,5] that may be partly
due to the proliferation of these cells in the skin
[12,13]. Maximal numbers of macrophages are present
at 24 h but by 48 h the majority of infiltrating cells are T
cells [5,7,14].
Recently elegant studies of cutaneous infection with
HSV-1 have suggested that HSV-specific cells that have
migrated to the site of Ag exposure, remain resident in the
skin following Ag-clearance [15,16]. These long-lived
skin resident cells provide a rapid response to subsequent
re-exposure to the same pathogen, presented by tissue
resident DC and could contribute to the initial steps of
activation and to the initiation of the inflammatory cas-
cade [15,16].
Older humans and mice have been shown to have defec-
tive DTH responses [17–19]. At first glance this appears
to suggest that this may reflect the development of
defective immune memory to antigen during ageing.
However as will be discussed later, the decreased mani-
festation of antigen-specific cutaneous immunity is actu-
ally due to altered coordination between innate and
acquired arms of the cutaneous immune system in older
subjects [11]. In order to fully appreciate the implica-
tions of this, it is first necessary to consider the data
available on defects of individual leukocyte populations
that accumulate during ageing.
Toll-like receptors and ageing
The endothelial activation and conditioning of the skin
environment at the site of antigenic challenge, which
enables the recruitment of leukocytes from the blood, is
considered to be due to the secretion of proinflammatory
cytokines by cells of the innate immune system that are in
turn activated by ‘danger signals’ [10,20,21]. Toll like
Current Opinion in Immunology 2011, 23:525–531
Recruited Recirculating
Monocytes Natural Killer Cells
Granulocytes Dendritic cells
-Basophilic
-Eosinophilic
-Neutrophilic
Mast cells ?Promonocytes
Epitheloid cells
T lymphocytes T lymphocytes
B lymphocytes
receptors (TLR) are one of the most important transdu-
cers of ‘danger signals’ [20], resulting from the presence of
antigen and trauma to the skin. TLRs are expressed by
various cells of the innate immune systems including
monocytes, macrophages (MF), dendritic cells (DC)
and Langerhans cells (LC) as well as keratinocytes.
Evidence in humans and mice suggest that TLR expres-
sion or TLR induced production of inflammatory
mediators by cells of the innate immune system is
reduced during ageing (reviewed in [22]). Furthermore
a recent study demonstrated the decreased production of
pro-inflammatory cytokines such as TNF-a, IL-6 and IL-
12 from circulating DCs in old individuals stimulated
with various TLR ligands [23]. It is possible therefore that
one reason for defective cutaneous immunity during
ageing may be related to defective conditioning of the
skin environment by innate cells resulting from defective
TLR signalling.
Skin APC and ageing
The main components of the innate immune system in
the skin are Langerhans cells, dermal dendritic cells and
skin resident macrophages. These antigen presenting
cells produce inflammatory mediators in response to
TLR signalling, present antigen and provide co-stimu-
lation to T cells both in the skin and in the draining lymph
node. A number of recent reviews have covered in detail
changes in the innate immune cells that occur with ageing
[24,25], this section highlights some of the recent studies
that are particularly relevant to the antigen presenting
cells in the skin.
In general, the number and phenotype of cutaneous DCs
are comparable in young and old subjects during ageing
however migration, phagocytosis and capacity to stimu-
late T cells may be decreased [24–26]. A study using a
mouse melanoma model by Grolleau-Julius et al. found
that aged DC have impaired capacity to migrate from the
periphery into the LN despite expressing equivalent
levels of CCR7 as young cells [27]. However even when
the defective migration was corrected these aged DC
were less efficient at inducing anti-tumour immunity
suggesting an additional functional defect that correlated
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with a selective reduced DC-SIGN expression [27]. Sim-
ilarly human DC from elderly individuals showed
impaired migration towards MIP-1b despite equivalent
CCR7 expression [28].
Plasmacytoid dendritic cells (PDC) are a unique dendritic
cell subset, which is present in the normal skin in very small
numbers. However, they play an important role in viral
infection (for example VZV) and inflammatory skin dis-
orders (such as psoriasis, lupus erythematosus and lichen
planus) [29]. PDCs have also been described in skin
tumours (melanoma, BCC, SCC, CTCL) [29]. Skin injury
(by tape striping or by chemical treatment) also results in
rapid recruitment of PDCs [30] and in rapid and transient
secretion of type I interferon that promotes wound healing
[31]. In contrast to classical DCs, there is clear evidence
that PDC cytokine secretion is reduced with age [23,32].
Jing et al. also observed that circulating PDC number and
IFN-a production decreased in older subjects [33]. The
evidence that older people often have problems with VZV
reactivation, causing shingles, supports the possibility of
the impaired function of PDC in the skin, either through
decreased migration, activation or cytokine secretion.
A number of macrophage functions decline with ageing,
including diminished TLR expression (or reduced cyto-
kine secretion in response to TLR stimulation), reduced
phagocytic capacity and a decline in secretion of chemo-
kines and cytokines (reviewed in [24]). In the DTH
model, there is decreased ability of macrophages in the
antigen-challenged skin of older humans to secrete
inflammatory cytokines such as TNF-a following antigen
challenge [11].
Langerhans cells are myeloid-derived dendritic cells that
reside in the epidermis, in close contact with keratino-
cytes. Until recently LC were considered to be the main
antigen presenting cell in the skin, responsible for pro-
moting immune response to invading pathogens [10].
The classical view is that LC capture and process
cutaneous antigens then migrate into the LN where they
present the antigen to T cells [10]. More recently it was
reported that Langerhans cells play a crucial role in the
induction of IL-22 secreting T cells (Th22) [34,35] that
play an important role in cutaneous immune responses.
Other studies have suggested that LC play an important
role in downregulating immune responses [36]. For
example, Langerhans cells are required for UV-radiation
induced suppression, and this immunological unrespon-
siveness is mediated through the induction of Tregs [37–
39]. The ability of LC to migrate to draining lymph nodes
has been shown to decline with age [40,41]. Collectively
these results suggest that a wide range of defects may
occur in innate populations of leucocytes in the skin
during ageing but it is not clear how this may lead to
the susceptibility of older humans or mice to skin infec-
tions or malignancy.
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Skin and old age Vukmanovic-Stejic et al. 527
Cutaneous T cells during ageing
Normal, healthy human skin contains large numbers of
antigen experienced CD4+ and CD8+ T cells [42,43].
According to some calculations there are approximately
20 billion skin-resident T cells in healthy human skin,
nearly twice the number present in circulation [43].
Schierli et al. suggested that the majority of human T
cells in healthy skin express CCR8 and act as immune
surveillance cells, which recognise peptide–MHC com-
plexes on epidermal APC and trigger an immune defense
program involving monocytes, granulocytes, inflamma-
tory T cells and antibodies [42]. In this scheme activated
immune surveillance T cells play a dual role. Through
the secretion of TNF-a and IFN-g after antigen chal-
lenge, they initiate inflammatory cascades that lead to the
recruitment of other leucocytes. Secondly, these cells
may migrate to the draining LN where they may pro-
liferate themselves or accelerate the activation of other
antigen-specific T and B cell responses. It is possible
that one of the reasons for impaired cutaneous immunity
in the elderly may be due to changes in the skin resident
T cells.
Repeated antigenic stimulation throughout life may com-
promise antigen-specific T cells in two ways [44]. First,
they may become functionally exhausted and lose essen-
tial functional activity that is necessary for immune
protection [45,46]. Functional exhaustion is a way of
limiting the magnitude of effector T cell responses and
is often associated with the increased expression of sur-
face inhibitory receptors. Although this may safeguard
against autoimmune responses, it may also compromise
effective immunity against infectious agents and tumours
[47]. Second, repeated T cell stimulation can lead to a loss
of replicative capacity of some antigen-specific T cell
populations as a result of telomere erosion and/or unre-
paired DNA damage (a process known as replicative
senescence) [48,49]. Interestingly, accelerated telomere
erosion has been observed during immune response in
the skin, because of inhibition of the enzyme telomerase,
by type I interferon [12]. It is not clear at present if skin
resident T cells, or those that are recruited during anti-
genic challenge, may be compromised by either exhaus-
tion or senescence in older humans and this requires
further investigation.
Regulatory T cells accumulate in the skin
during ageing
Regulatory T cells play a crucial role in regulating the
magnitude of an immune response. We and others have
shown that 5–10% of T cells resident in normal human
skin express Foxp3 and have other characteristics of
Tregs [11,13,50]. These regulatory cells also proliferate
in the skin during the course of a DTH response [13]. A
recent study has shown that Tregs (as well as responder T
cells) circulate between the skin and LNs and vice versa,
in the steady state and during an immune response [9].
Current Opinion in Immunology 2011, 23:525–531
528 Immune Senescence
These Tregs can directly inhibit both T cells and antigen
presenting cells (APC) such as dendritic cells and macro-
phages [51,52]. Using a mouse model of melanoma,
Richards et al. demonstrated that Tregs can suppress very
early stages of the inflammatory response after Ag chal-
lenge [53]. Following depletion of Tregs, there was a
significant increase in neutrophil infiltration, secondary to
increased concentrations of neutrophil chemoattractants
(CXCL1, CXCL2) [53].
Older mice and humans individuals have increased pro-
portion of Tregs in normal skin [11,54]. These Tregs may
interfere with the effective initial proliferation/function of
resident antigen-specific T cells, or they could inhibit the
activation of the innate immune response that may lead to
the decreased immunity in these individuals. The negative
effect of Treg accumulation on the induction of effective
immune responses in the skin is well documented in a
number of cancers. Increased numbers of Tregs have been
observed in primary melanoma, melanoma metastasis and
basal cell carcinoma [55,56,57]. Furthermore, in human
squamous cell carcinoma of the skin, 50 percent of T cells
that are present are Foxp3+ [57]. Topical treatment with
a TLR7 agonist imiquimod that has been shown to be an
effective therapy in these patients, reduces the percentage
of Treg and their suppressive function [57]. In addition,
Klages et al. have shown that in the mouse model of
melanoma, selective depletion of Foxp3+ cells synergises
with vaccination strategies to elicit anti-tumour responses
[58]. In a similar model Simon et al. demonstrated that
Tregs suppressed innate immune response and that their
removal improved tumour rejection [59]).
The reasons for and the mechanism by which Tregs
accumulate in the skin and other tissues of older humans
and mice is not clear [11,54,60]. It is known that Tregs
can be induced in the skin by UV irradiation, and that the
UV-induced Tregs then affect the function of dendritic
cells, through the secretion of IL-10, resulting in the
induction of more Tregs by these ‘tolerogenic’ DC
[52]. Alternatively, circulating Tregs may preferentially
home to the skin as a large proportion of them express
CLA. Collectively these data suggest that the accumu-
lation of Tregs in the skin during ageing may contribute
to the defective cutaneous immunity in these individuals
by inhibiting either the T cells themselves or cells of the
innate immune system.
Reduction in human antigen-specific
cutaneous immune response during ageing –
evidence for reduced immune surveillance
Previous studies indicated that old subjects have reduced
ability to mount cutaneous DTH reactions after chal-
lenge with recall antigens and that this occurs in both
humans and rodents [17–19,61]. This included decreased
erythema and induration at the site of antigenic challenge
as well as decreased infiltration of T cells as assessed by
Current Opinion in Immunology 2011, 23:525–531
immuno histology. Since the DTH response is widely
considered to reflect a secondary (memory) T cell
response to antigen, these results were thought to
indicate a general age-related decline in T cell-mediated
immunity [19,62]. In contrast, a recent study in humans
has shown that DTH responses to bacterial, fungal and
viral antigens are reduced with age, despite similar
responsiveness of circulating T cell to the same antigen
in vitro [11]. This suggests that the decreased cutaneous
reactivity is a defect in local and not systemic immunity
and highlights the possibility of defective migration of
specific T cells into the skin after antigenic challenge. An
age associated defect in cutaneous antigen-specific T cell
migration is supported by studies in the mouse model of
accelerated ageing (SAMP1 mice) where Toichi et al. also
observed defective T cell migration [18].
The decreased ability of T cells to migrate into the skin
after a DTH response in old humans was not found to be
due to defective chemokine receptor or integrin expres-
sion by circulating T cells [11]. Furthermore the T cells
from older humans also had unimpaired physical capa-
bility to migrate across monolayers of endothelial cells in
vitro [11]. Instead the reason for the reduced DTH
clinical and cellular response appears to be lack of acti-
vation of the endothelium. Activation of the endothelium
results in the upregulation of E-selectin, VCAM and
ICAM, adhesion molecules crucial for T cells transmigra-
tion into skin. TNF-a and IFN-g, are the main inducers
of the endothelial activation [63] and in the DTH
response of young humans, these cytokines were mainly
secreted by macrophages [11]. The secretion of these
cytokines was significantly reduced at the site of antigen
injection in the skin although macrophage numbers were
normal in older humans after antigen challenge [11].
The macrophages however were perfectly capable of
secreting these cytokines when isolated from the skin
and stimulated with TLR ligands in vitro, suggesting that
they were being inhibited in vivo. The importance of
TNF-a in effective cutaneous immunity is supported by
anecdotal evidence that rheumatoid arthritis patients on
anti-TNF-a therapy show increased susceptibility to skin
infections and cancers [64].
One explanation for the decreased secretion of pro-
inflammatory cytokines after cutaneous antigenic chal-
lenge in old humans may be that the increased proportion
of Tregs that are found in the skin of these individuals
both before and after antigenic challenge may inhibit
macrophage activation and cytokine secretion. Tregs
have been shown to inhibit TNF-a secretion and steer
macrophages towards and anti-inflammatory functional
profile [51].
Conclusion
In older humans, there is increased incidence of certain
cutaneous malignancies and infections that point to
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defective immunity in the skin. Immune ageing is a
multifactorial process and in the skin there is evidence
that various cells exhibit defects during ageing. The
DTH reaction, a memory T cell response in the skin is
also defective in older humans. However, the defect may
not be in the memory T cells themselves instead, con-
ditioning of the skin environment at the site of the
antigenic challenge is defective, resulting in suboptimal
endothelial activation that prevents circulating memory T
cells from homing to the appropriate location in the skin.
This decreased cutaneous response after antigenic chal-
lenge may be related to suppression of either the acquired
or innate arms of the immune response by Tregs that are
found at significantly higher numbers in the skin of older
humans. These finding raise the question of whether
modulating Treg activity in the skin may be a way to
boost cutaneous immunosurveillance of older humans
that may reduce the risk of developing malignancy or
infections in these individuals.
Acknowledgements
Authors would like to acknowledge support of the MRC UK (grant award
G0901102 to MV-S), BBSRC, British Skin Foundation and Dermatrust (to
AA) and National Institutes of Health (grant awards AG20719 and
AG03319, National Institute on Ageing to JN-Ž).
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