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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-specic 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)

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-specic T cell responses in the skin

Since the induction and amplication of cutaneous immunity is an integrated multistep process, in vivo experimental models are the most informative. A particularly useful experimental system is the delayed type hypersensitivity (DTH) response, where recall antigens are injected intradermally [46]. This is a classical model of an antigenspecic memory T cell (secondary) response since individuals (mice or humans) who have not been exposed to the antigen do not respond to the antigen challenge [47]. 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 [47]. There are some differences 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 inltrates are similar in both species [47]. While other experimental models for the study of cutaneous immunity 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-specic danger signals to recruit and activate cells of the innate immune system and at very early time points (46 h) the majority of inltrating cells are neutrophils [5]. This cellular inltration is dependent on the production of pro-inammatory 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 12 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, 23:525531

Current Opinion in Immunology 2011, 23:525531 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 bodys largest interface with the environment and its principal function is that of a barrier. It protects the organism by being impermeable to a multitude 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 adaptive pathways of immunity plays an important role in the initiation and amplication 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 cellulitis) and fungal infections (often candidaiasis) [1] and
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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 T lymphocytes Recruited Monocytes Granulocytes -Basophilic -Eosinophilic -Neutrophilic Mast cells Epitheloid cells T lymphocytes B lymphocytes Recirculating Natural Killer Cells Dendritic cells

?Promonocytes T lymphocytes

Adaptive

? 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 inammation in the skin [10]. The inltration of T cells during a DTH response is biphasic, comprising an early non-specic inltration of these cells that appear around dermal blood vessels approximately 12 h after challenge [7] and a later peak of antigenspecic 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 inltrating cells are T cells [5,7,14]. Recently elegant studies of cutaneous infection with HSV-1 have suggested that HSV-specic 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 inammatory cascade [15,16]. Older humans and mice have been shown to have defective DTH responses [1719]. At rst glance this appears to suggest that this may reect the development of defective immune memory to antigen during ageing. However as will be discussed later, the decreased manifestation of antigen-specic cutaneous immunity is actually due to altered coordination between innate and acquired arms of the cutaneous immune system in older subjects [11]. In order to fully appreciate the implications of this, it is rst necessary to consider the data available on defects of individual leukocyte populations that accumulate during ageing.

receptors (TLR) are one of the most important transducers 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 expression or TLR induced production of inammatory 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-inammatory cytokines such as TNF-a, IL-6 and IL12 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 inammatory mediators in response to TLR signalling, present antigen and provide co-stimulation 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 stimulate T cells may be decreased [2426]. 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 efcient at inducing anti-tumour immunity suggesting an additional functional defect that correlated
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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 proinammatory cytokines by cells of the innate immune system that are in turn activated by danger signals [10,20,21]. Toll like
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with a selective reduced DC-SIGN expression [27]. Similarly 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 inammatory skin disorders (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 cytokine secretion in response to TLR stimulation), reduced phagocytic capacity and a decline in secretion of chemokines 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 inammatory 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 keratinocytes. Until recently LC were considered to be the main antigen presenting cell in the skin, responsible for promoting 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 unresponsiveness 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 infections or malignancy.
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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 peptideMHC complexes on epidermal APC and trigger an immune defense program involving monocytes, granulocytes, inammatory 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 challenge, they initiate inammatory cascades that lead to the recruitment of other leucocytes. Secondly, these cells may migrate to the draining LN where they may proliferate themselves or accelerate the activation of other antigen-specic 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 compromise antigen-specic T cells in two ways [44]. First, they may become functionally exhausted and lose essential 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 surface 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-specic T cell populations as a result of telomere erosion and/or unrepaired 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 antigenic challenge, may be compromised by either exhaustion 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 510% 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].
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These Tregs can directly inhibit both T cells and antigen presenting cells (APC) such as dendritic cells and macrophages [51,52]. Using a mouse model of melanoma, Richards et al. demonstrated that Tregs can suppress very early stages of the inammatory response after Ag challenge [53]. Following depletion of Tregs, there was a signicant increase in neutrophil inltration, secondary to increased concentrations of neutrophil chemoattractants (CXCL1, CXCL2) [53]. Older mice and humans individuals have increased proportion of Tregs in normal skin [11,54]. These Tregs may interfere with the effective initial proliferation/function of resident antigen-specic 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 accumulation 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.

immuno histology. Since the DTH response is widely considered to reect 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 specic T cells into the skin after antigenic challenge. An age associated defect in cutaneous antigen-specic 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 expression by circulating T cells [11]. Furthermore the T cells from older humans also had unimpaired physical capability 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 activation of the endothelium. Activation of the endothelium results in the upregulation of E-selectin, VCAM and ICAM, adhesion molecules crucial for T cells transmigration 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 signicantly 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 proinammatory cytokines after cutaneous antigenic challenge 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-inammatory functional prole [51].

Reduction in human antigen-specic 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 challenge with recall antigens and that this occurs in both humans and rodents [1719,61]. This included decreased erythema and induration at the site of antigenic challenge as well as decreased inltration of T cells as assessed by
Current Opinion in Immunology 2011, 23:525531

Conclusion
In older humans, there is increased incidence of certain cutaneous malignancies and infections that point to
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Skin and old age Vukmanovic-Stejic et al. 529

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, conditioning 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 challenge may be related to suppression of either the acquired or innate arms of the immune response by Tregs that are found at signicantly higher numbers in the skin of older humans. These nding 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.

11. Agius E, Lacy KE, Vukmanovic-Stejic M, Jagger AL,  Papageorgiou AP, Hall S, Reed JR, Curnow SJ, FuentesDuculan J, Buckley CD et al.: Decreased TNF-{alpha} synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J Exp Med 2009, 206:1929-1940. A study investigating the basis for age-associated reductions in DTH responses in old individuals. Age-associated decreased T cell inltration was observed, secondary to reduced activation of the endothelium. Ageassociated reductions in TNF-a production in cutaneous macrophages and increase in cutaneous Treg cells are reported as possible causes. 12. Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M et al.: Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo. J Exp Med 2004, 199:1433-1443. 13. Vukmanovic-Stejic M, Agius E, Booth N, Dunne PJ, Lacy KE, Reed JR, Sobande TO, Kissane S, Salmon M, Rustin MH, Akbar AN: The kinetics of CD4Foxp3 T cell accumulation during a human cutaneous antigen-specic memory response in vivo. J Clin Invest 2008, 118:3639-3650. 14. Kenney RT, Rangdaeng S, Scollard DM: Skin blister immunocytology. A new method to quantify cellular kinetics in vivo. J Immunol Methods 1987, 97:101-110. 15. Wakim LM, Waithman J, van Rooijen N, Heath WR, Carbone FR:  Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 2008, 319:198-202. A study providing important insight into the priming and execution of antiviral immunity to a local viral infection. Using a model of herpes simplex virus reactivation to examine the stimulation of tissue-resident T cells during secondary challenge. The results revealed that memory CD8+ T cell responses can be initiated within peripheral tissues through a tripartite interaction that includes CD4+ T cells and recruited dendritic cells. These ndings support the existence of a response mechanism in extra-lymphoid tissues that can act to control localised infection. 16. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR,  Carbone FR: Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 2009, 10:524-530. Related to reference above. This study reports that memory CTLs in the skin remain in the tissue and maximise protective immunity to subsequent challenge with HSV-1. Using GFP expressing mice and serial transplantation of latently infected ganglia, the authors carry out an elegant set of experiments to demonstrate that HSV-specic cells reside in the skin near the primary site of HSV-1 infection. These tissue-resident memory T cells do not readily enter circulation once they establish residency in a given tissue and can proliferate locally after secondary viral challenge. 17. Vissinga C, Nagelkerken L, Zijlstra J, Hertogh-Huijbregts A, Boersma W, Rozing J: A decreased functional capacity of CD4+ T cells underlies the impaired DTH reactivity in old mice. Mech Ageing Dev 1990, 53:127-139. 18. Toichi E, Hanada K, Hosokawa T, Higuchi K, Hosokawa M, Imamura S, Hosono M: Age-related decline in humoral immunity caused by the selective loss of TH cells and decline in cellular immunity caused by the impaired migration of inammatory cells without a loss of TDTH cells in SAMP1 mice. Mech Ageing Dev 1997, 99:199-217. 19. Castle SC, Norman DC, Perls TT, Chang MP, Yoshikawa TT, Makinodan T: Analysis of cutaneous delayed-type hypersensitivity reaction and T cell proliferative response in elderly nursing home patients: an approach to identifying immunodecient patients. Gerontology 1990, 36:217-229. 20. Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004, 5:987-995. 21. Matzinger P: An innate sense of danger. Ann NY Acad Sci 2002, 961:341-342. 22. Shaw AC, Panda A, Joshi SR, Qian F, Allore HG, Montgomery RR: Dysregulation of human Toll-like receptor function in aging. Ageing Res Rev 2010, 10:346-353. 23. Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E et al.: Age-associated decrease in TLR function in primary human dendritic cells Current Opinion in Immunology 2011, 23:525531

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-Z).

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