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Review

Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis

by
Trung T. Vu
1,2,
Hanako Koguchi-Yoshioka
2,3 and
Rei Watanabe
2,3,*
1
Department of Cutaneous Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
2
Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka 565-0871, Japan
3
Department of Integrative Medicine for Allergic and Immunological Diseases, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka 565-0871, Japan
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(17), 3822; https://doi.org/10.3390/jcm10173822
Submission received: 22 July 2021 / Revised: 20 August 2021 / Accepted: 21 August 2021 / Published: 26 August 2021
(This article belongs to the Special Issue Psoriasis and Psoriatic Arthritis: How to Treat in the Era of Biologics and Small Molecule Inhibitors?)
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Abstract

:
Tissue-resident memory T cells (TRM) stay in the peripheral tissues for long periods of time, do not recirculate, and provide the first line of adaptive immune response in the residing tissues. Although TRM originate from circulating T cells, TRM are physiologically distinct from circulating T cells with the expression of tissue-residency markers, such as CD69 and CD103, and the characteristic profile of transcription factors. Besides defense against pathogens, the functional skew of skin TRM is indicated in chronic skin inflammatory diseases. In psoriasis, IL-17A-producing CD8+ TRM are regarded as one of the pathogenic populations in skin. Although no licensed drugs that directly and specifically inhibit the activity of skin TRM are available to date, psoriatic skin TRM are affected in the current treatments of psoriasis. Targeting skin TRM or using TRM as a potential index for disease severity can be an attractive strategy in psoriasis.

1. Introduction

Once the immune system encounters antigens, memory T cells are generated from the naïve T cells and facilitate a prompt response to the re-exposure of the same antigens. Two populations of memory T cells have been defined from human blood circulation: effector memory T cells (TEM) and central memory T cells (TCM) [1]. TEM are also dominant in peripheral non-lymphoid tissues and TCM have an affinity for secondary lymphoid organs [2,3]. Furthermore, research on murine infectious disease models has revealed that a subpopulation of TEM found in peripheral tissues remain in the same tissues for long periods without recirculation after cure of infection [4,5,6]. These findings led to the establishment of the new population of memory T cells, tissue-resident memory T cells (TRM).
TRM are superior to their circulating memory counterparts in their ability to provide the local adaptive cellular defense [7,8,9,10,11]. They can respond to the local antigen re-exposure without the recruitment of circulating T cells to the tissue [12]. In addition, recent studies suggest TRM also contribute to systemic immune responses upon subsequent exposure to specific antigens by proliferating and baring circulating populations, such as TCM and TEM [13,14].
The existence and functional activities of TRM were initially investigated in barrier tissues, such as the gut [6,15], skin [4,5,12,16,17], respiratory tract [18,19], and reproductive tract [20,21], in the context of local defense against pathogens in infectious diseases. However, their roles are now recognized in various conditions, including cancer immunity, tissue-specific autoimmune diseases, and chronic inflammatory diseases both in barrier and non-barrier tissues [22].
Skin TRM are among the intensively studied TRM populations not only in murine models but also in humans. The human skin contains an estimate of 20 billion T cells, doubling those in the circulation [23], and over half of these T cells show the TRM phenotype [24]. Besides infectious diseases, the involvement of skin TRM has been reported in allergic contact hypersensitivity [25]; fixed drug eruption [26]; cutaneous malignancies, including malignant melanoma [27,28] and cutaneous T-cell lymphoma [24,29]; and chronic inflammatory diseases, such as vitiligo, alopecia, and psoriasis [30,31].
In this review, we provide an overview of the general characteristics of TRM. Then, narrowing our focus to skin TRM in humans, we summarize the involvement of skin TRM in cutaneous disorders, especially psoriasis. We also mention the possibility of engaging TRM as a disease index and treatment target in psoriasis. Since CD8+ TRM are the best-characterized population, we focus on CD8+ TRM and describe this population as TRM in this review unless otherwise mentioned.

2. The Characteristics of TRM

T cells in the neonatal murine skin are predominant with dendritic epidermal T cells (DETCS) with restricted antigenic specificity [32], and neonatal human skin holds only a few T cells [24]. Thus, TRM are assumed to develop from circulating T cells according to repeated antigen exposure. In the local inflammation caused by specific antigens, the robustly expanded effector T cells emerge in the circulation and the affected tissues, and both TCM and TRM are assumed to arise from a part of these effector T cells [25,33].
The general characteristics of TRM across the tissues include the loss of migration and the gain of retention. The development and maintenance of these characteristics in TRM are driven by complex factors, such as cytokine and chemokine receptors, the other cell-surface molecules being responsible for tissue homing and retention, and transcription factors (Figure 1).

2.1. Cell Surface Molecules

While homing molecules including chemokine receptors are diverse depending on the target peripheral tissues, the molecules related to tissue retention seem to be shared among various tissues. In general, TRM lack the expression of the secondary lymphoid homing molecules CC-chemokine receptor 7 (CCR7) and L-selectin, which are expressed on TCM and naïve T cells [1]. The tissue retention molecules CD69 and CD103 (αE integrin) are widely recognized as the markers for TRM. CD103 is a ligand of E-cadherin that is expressed on epithelial cells [34], and CD69 interferes with sphingosine-1-phosphate (S1P) receptor-1, which allows the cells to exit from peripheral tissues by sensing the density of S1P [35]. CD69 also reportedly regulates the uptake of L-tryptophan and the intracellular quantity of L-tryptophan-derived activator of the aryl hydrocarbon receptor (AhR) [36], which is reportedly involved in the persistence of TRM [32]. These functions would explain at least partially the importance of these molecules in tissue retention. However, their expression varies, possibly depending on the tissues and the causes of TRM development. TRM lacking CD103 expression have been described in some peripheral tissues and secondary lymphoid organs [37,38] and CD103+ TRM can be found in the dermis and adult central nervous system where E-cadherin is absent, implying that binding to E-cadherin is not required for the persistence of TRM in peripheral tissues [24,39]. Although CD69 is expressed on the majority of TRM in various peripheral tissues, TRM negative for CD69 expression are also noted [33]. We thus have to take into account that these two molecules are not able to cover TRM universally.

2.2. Transcription Factors

Transcriptional regulation is also presumably common among TRM in various tissues. For instance, the expression of AhR is increased in skin TRM as compared with naïve T cells and splenic T cells, possibly favoring the maintenance of skin TRM [32]. Rapamycin inhibits the formation of TRM in the intestinal and vaginal mucosa, highlighting a positive link of mammalian target of rapamycin and the downstream transcription factors with the formation of TRM [40]. The maintenance of lung TRM may be related to Notch signaling, including the upregulation of the downstream transcription factor RBPJ [41]. The augmented uptake of exogenous lipids accompanied by the upregulation of fatty acid binding proteins (FABPs) 4 and 5 is one of the characteristic processes involved in the generation and maintenance of skin TRM [42]. Hypoxia-inducible factor-1α, which is a transcription factor in the downstream of FABP5 signaling, reportedly promotes the residency and anti-tumor function of tumor-infiltrating T cells in the murine malignancy model [43]. The downregulation of T-box transcription factors T-bet and EOMES [44] and the upregulation of Blimp-1, Hobit [45], and Runx3 [46,47] have also been reported to be involved in the differentiation and/or maintenance of TRM.

2.3. Skin-Homing Molecules

In addition to the shared characteristics of various TRM, skin TRM are shown to have their own homing molecules. As one of skin’s homing molecules, cutaneous lymphocyte-associated antigen (CLA) binds to E-selectin and P-selectin and allows the cells to migrate into skin [23]. The chemokine receptors CCR4, CCR8, CCR10, CXCR3, and CXCR6 are also regarded as important skin-homing and/or retention molecules for at least some skin T cells [16,48,49,50,51,52].

2.4. Fate Decision of TRM

How the fate of TRM differentiation is decided remains an unsolved question. TRM reportedly derive from circulating T cells lacking high expression of the killer cell lectin-like receptor subfamily G member 1 (KLRG1), which is regarded as a terminal differentiation marker [16,47]. Another report demonstrates that the effector T cells with enriched expression of TRM-associated genes, such as Itgae (CD103), Itga1 (CD49a), Cd101, Ahr, and Fabp5, already exist as memory precursor cells and preferentially differentiate into TRM [53], suggesting that the fate of TRM is at least partially decided in the early stage of adoptive immune memory formation. On the other hand, the time-course single-cell RNA-sequencing analysis in a murine model with lymphocytic-choriomeningitis-virus infection revealed that the transcriptional characteristics of TRM can be detected from gut-infiltrating T cells at the earliest 4 days after infection, and the characteristics are distinct from those found in splenic T cells [54], implying that the TRM differentiation program is initiated after the cells enter the specific peripheral tissues. Further elucidation of the TRM differentiation mechanism will require further research.

3. Human Skin TRM

In general, human TRM and murine TRM share core transcriptional, phenotypic, and functional profiles, including the almost global expression of CD69 and dominant CD103 expression in CD8 fractions [45,55,56,57]. In patients with cutaneous T-cell lymphoma (CTCL), the treatment with alemtuzumab, which depletes circulating T cells and spares the TRM, does not result in serious infection [58], implying the role of skin TRM in protective immunity. The TRM phenotype of the malignant cells in CTCL is related to the clinical manifestation of well-demarcated lesions, suggesting that the sessile property of TRM also exists in humans [24]. In vitro experiments suggest skin TRM maintain the production of IL-17A and IFN-γ in reaction with pathogen challenges through aging [59]. Using transcriptomic and functional data, human TRM are found to abolish their senescent phenotype and survive for over 10 years in specific circumstances [46], replicating the longevity of TRM in humans.
However, TRM in humans are presumably more diverse and widely distributed. For instance, CD4+ TRM are found in both the epidermis and dermis in humans, although murine skin CD4+ TRM are predominantly found in dermis [17,24,60,61]. TRM are also found in secondary lymphoid organs, such as the spleen, lymph nodes, and tonsils in humans [55,56].
The factors that may cause the difference between human skin TRM properties and those observed in laboratory mice may include the following: (1) the thick epidermis with abundant niche for TRM [24,62]; (2) the low density of hair follicles that express cytokines important for TRM migration and survival, including IL-7 and IL-15 [63,64]; (3) the frequent exposure to foreign antigens; (4) the small population of γδT cells with the lack of DETC in the human epidermis [65] (however, we do not know whether the recently identified αβγδT cell population in fetal skin can replace DETC) [66]. The longer survival period of human TRM compared to murine life span [46] may also cause difficulty in adapting the findings in murine models to human biology.
The involvement of skin TRM is highlighted in chronic inflammatory disorders and cutaneous malignancies. In the lesional skin of alopecia areata, TRM with the ability to produce granzyme B are dominant and related to disease prognosis, implying their involvement in the pathogenesis [67]. Intraepidermal IFN-γ-producing TRM are enriched in the cured sites of fixed drug eruption [26], suggesting the contribution of this fraction to the reproducible property. In patients with atopic dermatitis, cutaneous TRM with the production of IL-4 and IL-13 are also indicated to be involved in the disease pathogenesis [68]. Dermal TRM are increased with the production potential of perforin, granzyme B, and IFN-γ in vitiligo [30,69], which are presumably specific for melanocyte antigens. In malignant melanoma, skin TRM provide protection against tumor regrowth and are involved in vitiligo formation, suggestive of their specific reactivity against melanoma antigens [70]. Better understanding of cutaneous TRM will pave the way for novel management and treatment of skin diseases.
The methodologies for evaluating skin TRM are summarized in Table 1. In the translational research field, one of the most popular methods for analyzing TRM is fluorescence-activated cell sorting (FACS) analysis. However, conducting this method from biopsied skin specimens is not practical in the daily clinical settings considering the burden for both patients and clinicians. Immunohistochemistry (IHC) and/or immunofluorescence (IF) for TRM-related molecules, such as CD3, CD8, CD69, and CD103, on the residual biopsy specimens carried out for diagnosis is probably more feasible to date. To establish non-invasive methods for predicting the activities of skin TRM, such as analyzing tape-stripped or surface-swabbed samples, will require further research.

4. Skin TRM in the Pathogenesis of Psoriasis

Psoriasis, hereafter referred to as plaque psoriasis, is an immune-mediated chronic inflammatory skin disorder characterized by well-demarcated persistent scaly indurated erythematous plaques. The contributions of environment [71], hereditary predisposition [72], and autoantigens [73] are implied to be involved in disease development. Circulating T cells were previously regarded as responsible for the lesion formation in psoriasis. However, the inhibition of E-selectin, which is required for T-cell migration from the blood stream to skin, was noted to be ineffective [74]. Another blocking strategy of T-cell migration by the biologics targeting CD11a also did not show dramatic efficacy [75]. However, in a humanized murine model where psoriatic nonlesional skin specimens are grafted to immunodeficient mice [76], the healthy-appearing nonlesional skin grafts spontaneously develop psoriatic disease, suggesting that the cells residing in the nonlesional skin are sufficient for the development of psoriatic disease. These results have led to the theory that TRM may play a crucial role in the pathogenesis of psoriasis.
The fate of skin TRM is affected by the skin microenvironment, and in psoriasis, this is also the case. Several skin-constituting factors have been reported to support the development and persistence of IL-17A-producing TRM in psoriasis. Keratinocytes in disease-naïve sites of psoriasis upregulate the expression of chemokines, such as CCL20 upon stimulation by skin commensal fungi [77]. Since CCL20 is a ligand for CCR6, which is a signature molecule of IL-17A-producing T cells, the activated keratinocytes in the disease-naïve sites of psoriasis are to recruit IL-17A-producing T cells to the disease-naïve sites, leading to the accumulation of IL-17A-producing TRM [77]. In turn, IL-17A from TRM stimulates keratinocytes to express CCL20, further accelerating the recruitment of CCR6+ cells [78]. In the resolved skin, the continuous production of IL-23 and IL-15 from Langerhans cells presumably support the maintenance of IL-17A-producing TRM in the epidermis [79]. The reduced repertoire of IL-17A-producing T cells in the resolved skin, which has been observed in different psoriatic patients, implies the existence of common antigens that drive the accumulation of psoriatic TRM [80]. Several potential autoantigens have been reported in psoriasis (Figure 2). For example, cationic antimicrobial peptide LL-37 produced by various cells including keratinocytes binds self-DNA and triggers the activation of plasmacytoid dendritic cells (pDC) and TNF/iNOS-producing dendritic cells (TIP-DC) [81,82]. A disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) in complex with HLA-C*06:02 on the surface of melanocytes confers epidermal CD8+ T-cell response [83]. Neo-lipid antigens generated by phospholipase A2 group 4D (PLA2G4D) from mast cells and keratinocytes trigger the CD1a-reactive T cells to produce IL-17A and IL-22 [84]. Keratin 17, a human epidermal keratin that shares a sequential homology with streptococcal M protein, is recognized by HLA-Cw*0602-restricted IFN-γ-producing CD8+ T cells [85,86]. Taken together, these results suggest the synchronizing roles of the skin microenvironment in the development and persistence of pathogenic cutaneous TRM.
In the lesional skin of patients with psoriasis, TRM consist of both CD4 and CD8 fractions, which synchronize the elevated immune response by the increased expression of inflammatory cytokines, such as IL-17A, IL-22, and IFN-γ [62,80,87,88]. While IL-17A-producing CD4+ TRM also exist in healthy skin, the enrichment of CD8+ TRM producing IL-17A in the epidermis is one of the characteristics of psoriasis [87,88]. In disease-naïve skin that has never experienced disease formation, IL-17A production is augmented by TRM [77], and the increase in IL-17A-producing CD8+ TRM at the dispense of IFN-γ-producing TRM occurs according to disease duration [88].
IFN-γ-producing TRM are also dominant in the epidermis and express the complex of CD49a–CD29, also known as very late antigen 1 (VLA-1) or α1β1 integrin [76]. CD49a+ TRM are involved in the pathogenesis of psoriasis. The number of epidermal CD8+CD49a+ TRM correlates with the severity of the disease [89], and an experimental blockade of CD49a in mice transplanted with psoriatic skin reduces the disease formation [76]. However, since the blockade of whole CD8+ T cells almost completely prevents disease development in the similar psoriatic skin-engrafted murine model [90], CD49a+ TRM with IFN-γ production are not likely the key population for disease development, while the CD8+ T cell population likely includes a critical fraction for disease pathogenesis. In fact, CD8+ TRM without the expression of CD49a are defined as an IL-17A-producing TRM subset [30].
Successful treatment with an IL-17A-targeting biologics results in a decreased number of IL-17A-producing TRM in resolved skin, but the frequency of these cells is not altered within the remaining T cells [91]. Another study on residual psoriasis after the use of biologics revealed a decrease in keratinocyte proliferation. However, the percentage of IL-17A-producing CD103+ TRM was not significantly reduced after the treatments [92]. Similarly, a new normal in the persistence of IL-17A-producing TRM with CCR6 and IL-23R expression in the resolved skin has been established [62,80]. IL-17A-producing CD8+ TRM and IL-22-producing CD4+ TRM remain in the psoriatic epidermis for as long as six years after starting the successful TNF-α-targeting treatment [62]. Taken together, these findings highlight the essential standing point of IL-17A-producing TRM as one of the pathogenic populations of skin TRM in psoriasis.

5. Targeting Skin TRM in the Management of Psoriasis

Regardless of the persistence of this population by various treatments in psoriasis, many of the current and upcoming therapeutics in clinical practice presumably exert an indirect influence on cutaneous IL-17A-producing TRM. Since the remission period after successful treatments inversely correlates with the relative IL-17 signaling of the resolved skin compared to IL-10 and IFN-γ signaling [93], the relative reduction, if not elimination, of IL-17A-producing TRM may be of help in controlling psoriatic disease activity.
Biologics targeting the IL-17 pathway reportedly reduce IL-17 signaling and the amount of T cells in the lesion [94]. Furthermore, the biologics targeting IL-23 decrease this fraction from the lesion more strongly compared to those targeting IL-17A [95]. Ultraviolet irradiation leads to the diminishment of IL-17A-producing T cells in skin [96], and this T-cell fraction includes TRM. Topical vitamin D analogues and corticosteroids reportedly reduce the lesional IL-17A-producing TRM, possibly including pathogenic TRM [97,98]. Retinoic acid prevents Th17 differentiation and possibly promotes the properties of regulatory T cells [99,100]. As the oral phosphodiesterase 4 inhibitor (PDE4i) diminishes the pro-inflammatory cytokine production from circulating T cells [101], the function of both topical and systemic PDE4i could be revisited from the perspective of skin TRM. An AhR agonist modulates the Th17 property of T cells, and the efficacy of its topical form possibly affects IL-17A-producing T cells in skin, including TRM [102].
Proof-of-concept approaches that directly and exclusively target pathogenic populations of TRM should be subjected to further studies. The candidate strategies might include the inhibition of the pathways involved in IL-15 signaling to perturb the survival of pathogenic TRM and the blockade of the pathways processing fatty acids to suppress the lipid metabolism of pathogenic TRM. Targeting the transcription factors specified for differentiation and maintenance of pathogenic TRM is also an attractive strategy. However, although the risk of targeting these populations of TRM is unknown, it may cause the loss of local immune memory against pathogens in the skin. Since the characteristic cell surface molecules and transcription factors found in TRM properties can be overlapped with the sessile properties of other cell types, such as innate lymphoid cells and B cells [103,104], the strategies targeting TRM might also affect the other tissue-sessile immunity. Specific treatment targets for psoriatic dysfunctional TRM, excluding the other TRM and skin-resident immune cells, would be ideal.

6. Conclusions

Extensive studies with rigorous methodologies have broadened our knowledge on TRM in general and those residing in the skin in particular (Table 1). The involvement of skin TRM in the pathogenesis of skin diseases is also being elucidated. Several key points are highlighted below:
  • TRM originate from circulating T cells, do not recirculate, and provide the first line of adaptive cellular defense in the residing tissues.
  • The functional skew of skin TRM is indicated in chronic skin inflammatory diseases.
  • In psoriasis, IL-17-A-producing CD8+ TRM may be among the pathogenic populations in the skin.
  • Pathogenic populations of skin TRM can be targeted in the current and future treatments of psoriasis. Skin TRM can also serve as a potential index of the disease.
Further studies on TRM will advance the management of not only psoriasis but other diseases in which this subset of T cells plays a role.
Table
Table 1. Several major findings related to methodologies used in research on humans.
Table 1. Several major findings related to methodologies used in research on humans.
Key FindingsMajor Methodologies
A role of skin TRM in protective immunity in humansFACS[58]
Skin TRM with the potential of producing cytokines are infiltrated in the lesion of patients with GVHDFC, single-cell TCR sequencing, and IF[46]
Cells residing in nonlesional skin are sufficient, and the recruitment of circulating cells is not necessary for the development of psoriatic diseaseTransplantation, FC, quantitative RT-PCR, and IHC[76]
CD8+ TRM producing IL-17A in the epidermis is one of the characteristics in psoriasisFC and IHC[87]
The increase in IL-17A-producing CD8+ TRM during the distribution of IFN-γ-producing TRM occurs according to psoriasis durationFC and IF[88]
The successful treatment with IL-17A-targeting biologics results in a decreased number of IL-17A-producing CD8+ TRM in resolved psoriatic skin, but the frequency of these cells is not alteredFC, IHC, and IF[91]
IL-17A-producing CD8+ TRM and IL-22-producing CD4+ TRM remain in the psoriatic epidermis for as long as six years after starting the successful TNF-α-targeting treatmentFC, quantitative RT-PCR, and IF[62]
FC: flow cytometry, TCR: T-cell receptor, RT-PCR: reverse transcription polymerase chain reaction, IF: immunofluorescence, IHC: immunohistochemistry.

Author Contributions

Conceptalization, T.T.V., H.K.-Y. and R.W.; writing—original draft preparation, T.T.V.; writing—review and editing T.T.V., H.K.-Y. and R.W.; visualization, T.T.V., H.K.-Y. and R.W.; supervision, R.W. All authors have read and agreed to the published version of the manuscript.

Funding

T.T.V. is funded by Kishimoto Foundation Fellowship.

Conflicts of Interest

R.W. received lecture fees from the companies Abbvie, Eli Lilly, Janssen Pharmaceuticals, Kyowa Kirin, Maruho, and Novartis, and a research grant from the companies Maruho and Janssen Pharmaceuticals. The funders have no role in the writing or in the decision to publish this manuscript.

References

  1. Sallusto, F.; Lenig, D.; Förster, R.; Lipp, M.; Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999, 401, 708–712. [Google Scholar] [CrossRef]
  2. Masopust, D.; Vezys, V.; Marzo, A.L.; Lefrançois, L. Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue. Science 2001, 291, 2413–2417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Reinhardt, R.L.; Khoruts, A.; Merica, R.; Zell, T.; Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 2001, 410, 101–105. [Google Scholar] [CrossRef] [PubMed]
  4. Gebhardt, T.; Wakim, L.M.; Eidsmo, L.; Reading, P.C.; Heath, W.R.; Carbone, F.R. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 2009, 10, 524–530. [Google Scholar] [CrossRef]
  5. Wakim, L.M.; Waithman, J.; van Rooijen, N.; Heath, W.R.; Carbone, F.R. Dendritic Cell-Induced Memory T Cell Activation in Nonlymphoid Tissues. Science 2008, 319, 198–202. [Google Scholar] [CrossRef] [Green Version]
  6. Masopust, D.; Choo, D.; Vezys, V.; Wherry, E.J.; Duraiswamy, J.; Akondy, R.; Wang, J.; Casey, K.A.; Barber, D.L.; Kawamura, K.S.; et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 2010, 207, 553–564. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Khalil, S.; Bardawil, T.; Kurban, M.; Abbas, O. Tissue-resident memory T cells in the skin. Inflamm. Res. 2020, 69, 245–254. [Google Scholar] [CrossRef]
  8. Watanabe, R. Protective and pathogenic roles of resident memory T cells in human skin disorders. J. Dermatol. Sci. 2019, 95, 2–7. [Google Scholar] [CrossRef] [Green Version]
  9. Schenkel, J.M.; Masopust, D. Tissue-Resident Memory T Cells. Immunity 2014, 41, 886–897. [Google Scholar] [CrossRef] [Green Version]
  10. Mueller, S.N.; Mackay, L.K. Tissue-resident memory T cells: Local specialists in immune defence. Nat. Rev. Immunol. 2016, 16, 79–89. [Google Scholar] [CrossRef]
  11. Carbone, F.R. Tissue-Resident Memory T Cells and Fixed Immune Surveillance in Nonlymphoid Organs. J. Immunol. 2015, 195, 17–22. [Google Scholar] [CrossRef] [Green Version]
  12. Jiang, X.; Clark, R.A.; Liu, L.; Wagers, A.J.; Fuhlbrigge, R.C.; Kupper, T.S. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 2012, 483, 227–231. [Google Scholar] [CrossRef] [PubMed]
  13. Behr, F.M.; Parga-Vidal, L.; Kragten, N.A.M.; van Dam, T.J.P.; Wesselink, T.H.; Sheridan, B.S.; Arens, R.; van Lier, R.A.W.; Stark, R.; van Gisbergen, K.P.J.M. Tissue-resident memory CD8+ T cells shape local and systemic secondary T cell responses. Nat. Immunol. 2020, 21, 1070–1081. [Google Scholar] [CrossRef] [PubMed]
  14. Fonseca, R.; Beura, L.K.; Quarnstrom, C.F.; Ghoneim, H.E.; Fan, Y.; Zebley, C.C.; Scott, M.C.; Fares-Frederickson, N.J.; Wijeyesinghe, S.; Thompson, E.A.; et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat. Immunol. 2020, 21, 412–421. [Google Scholar] [CrossRef] [PubMed]
  15. Masopust, D.; Vezys, V.; Wherry, E.J.; Barber, D.L.; Ahmed, R. Cutting Edge: Gut Microenvironment Promotes Differentiation of a Unique Memory CD8 T Cell Population. J. Immunol. 2006, 176, 2079–2083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Mackay, L.K.; Rahimpour, A.; Ma, J.Z.; Collins, N.; Stock, A.T.; Hafon, M.-L.; Vega-Ramos, J.; Lauzurica, P.; Mueller, S.N.; Stefanovic, T.; et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 2013, 14, 1294–1301. [Google Scholar] [CrossRef]
  17. Gebhardt, T.; Whitney, P.G.; Zaid, A.; Mackay, L.K.; Brooks, A.G.; Heath, W.R.; Carbone, F.R.; Mueller, S.N. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 2011, 477, 216–219. [Google Scholar] [CrossRef]
  18. Teijaro, J.R.; Turner, D.; Pham, Q.; Wherry, E.J.; Lefrançois, L.; Farber, D.L. Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection. J. Immunol. 2011, 187, 5510–5514. [Google Scholar] [CrossRef] [Green Version]
  19. Anderson, K.G.; Sung, H.; Skon, C.N.; Lefrancois, L.; Deisinger, A.; Vezys, V.; Masopust, D. Cutting Edge: Intravascular Staining Redefines Lung CD8 T Cell Responses. J. Immunol. 2012, 189, 2702–2706. [Google Scholar] [CrossRef] [Green Version]
  20. Schenkel, J.M.; Fraser, K.A.; Vezys, V.; Masopust, D. Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 2013, 14, 509–513. [Google Scholar] [CrossRef] [Green Version]
  21. Iijima, N.; Iwasaki, A. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 2014, 346, 93–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Sasson, S.C.; Gordon, C.L.; Christo, S.N.; Klenerman, P.; Mackay, L.K. Local heroes or villains: Tissue-resident memory T cells in human health and disease. Cell. Mol. Immunol. 2020, 17, 113–122. [Google Scholar] [CrossRef] [PubMed]
  23. Clark, R.A.; Chong, B.; Mirchandani, N.; Brinster, N.K.; Yamanaka, K.; Dowgiert, R.K.; Kupper, T.S. The Vast Majority of CLA+ T Cells Are Resident in Normal Skin. J. Immunol. 2006, 176, 4431–4439. [Google Scholar] [CrossRef] [Green Version]
  24. Watanabe, R.; Gehad, A.; Yang, C.; Scott, L.L.; Teague, J.E.; Schlapbach, C.; Elco, C.P.; Huang, V.; Matos, T.R.; Kupper, T.S.; et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci. Transl. Med. 2015, 7, 279ra39. [Google Scholar] [CrossRef] [Green Version]
  25. Gaide, O.; Emerson, R.O.; Jiang, X.; Gulati, N.; Nizza, S.; Desmarais, C.; Robins, H.; Krueger, J.G.; Clark, R.A.; Kupper, T.S. Common clonal origin of central and resident memory T cells following skin immunization. Nat. Med. 2015, 21, 647–653. [Google Scholar] [CrossRef] [PubMed]
  26. Mizukawa, Y.; Yamazaki, Y.; Teraki, Y.; Hayakawa, J.; Hayakawa, K.; Nuriya, H.; Kohara, M.; Shiohara, T. Direct Evidence for Interferon-γ Production by Effector-Memory-Type Intraepidermal T Cells Residing at an Effector Site of Immunopathology in Fixed Drug Eruption. Am. J. Pathol. 2002, 161, 1337–1347. [Google Scholar] [CrossRef]
  27. Amsen, D.; van Gisbergen, K.P.J.M.; Hombrink, P.; van Lier, R.A.W. Tissue-resident memory T cells at the center of immunity to solid tumors. Nat. Immunol. 2018, 19, 538–546. [Google Scholar] [CrossRef]
  28. Edwards, J.; Wilmott, J.S.; Madore, J.; Gide, T.N.; Quek, C.; Tasker, A.; Ferguson, A.; Chen, J.; Hewavisenti, R.; Hersey, P.; et al. CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti–PD-1 Treatment. Clin. Cancer Res. 2018, 24, 3036–3045. [Google Scholar] [CrossRef] [Green Version]
  29. Vieyra-Garcia, P.; Crouch, J.D.; O’Malley, J.T.; Seger, E.W.; Yang, C.H.; Teague, J.E.; Vromans, A.M.; Gehad, A.; Win, T.S.; Yu, Z.; et al. Benign T cells drive clinical skin inflammation in cutaneous T cell lymphoma. JCI Insight 2019, 4, e124233. [Google Scholar] [CrossRef]
  30. Cheuk, S.; Schlums, H.; Gallais Sérézal, I.; Martini, E.; Chiang, S.C.; Marquardt, N.; Gibbs, A.; Detlofsson, E.; Introini, A.; Forkel, M.; et al. CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin. Immunity 2017, 46, 287–300. [Google Scholar] [CrossRef] [Green Version]
  31. Xing, L.; Dai, Z.; Jabbari, A.; Cerise, J.E.; Higgins, C.A.; Gong, W.; de Jong, A.; Harel, S.; DeStefano, G.M.; Rothman, L.; et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med. 2014, 20, 1043–1049. [Google Scholar] [CrossRef] [Green Version]
  32. Zaid, A.; Mackay, L.K.; Rahimpour, A.; Braun, A.; Veldhoen, M.; Carbone, F.R.; Manton, J.H.; Heath, W.R.; Mueller, S.N. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl. Acad. Sci. USA 2014, 111, 5307–5312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Steinert, E.M.; Schenkel, J.M.; Fraser, K.A.; Beura, L.K.; Manlove, L.S.; Igyártó, B.Z.; Southern, P.J.; Masopust, D. Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance. Cell 2015, 161, 737–749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Cepek, K.L.; Shaw, S.K.; Parker, C.M.; Russell, G.J.; Morrow, J.S.; Rimm, D.L.; Brenner, M.B. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 1994, 372, 190–193. [Google Scholar] [CrossRef]
  35. Mackay, L.K.; Braun, A.; Macleod, B.L.; Collins, N.; Tebartz, C.; Bedoui, S.; Carbone, F.R.; Gebhardt, T. Cutting Edge: CD69 Interference with Sphingosine-1-Phosphate Receptor Function Regulates Peripheral T Cell Retention. J. Immunol. 2015, 194, 2059–2063. [Google Scholar] [CrossRef] [Green Version]
  36. Cibrian, D.; Saiz, M.L.; De La Fuente, H.; Sánchez-Díaz, R.; Moreno-Gonzalo, O.; Jorge, I.; Ferrarini, A.; Vázquez, J.; Punzón, C.; Fresno, M.; et al. CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat. Immunol. 2016, 17, 985–996. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Bergsbaken, T.; Bevan, M.J. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. Nat. Immunol. 2015, 16, 406–414. [Google Scholar] [CrossRef]
  38. Schenkel, J.M.; Fraser, K.A.; Masopust, D. Cutting Edge: Resident Memory CD8 T Cells Occupy Frontline Niches in Secondary Lymphoid Organs. J. Immunol. 2014, 192, 2961–2964. [Google Scholar] [CrossRef] [PubMed]
  39. Wakim, L.M.; Woodward-Davis, A.; Bevan, M.J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc. Natl. Acad. Sci. USA 2010, 107, 17872–17879. [Google Scholar] [CrossRef] [Green Version]
  40. Sowell, R.T.; Rogozinska, M.; Nelson, C.E.; Vezys, V.; Marzo, A.L. Cutting Edge: Generation of Effector Cells That Localize to Mucosal Tissues and Form Resident Memory CD8 T Cells Is Controlled by mTOR. J. Immunol. 2014, 193, 2067–2071. [Google Scholar] [CrossRef]
  41. Hombrink, P.; Helbig, C.; Backer, R.A.; Piet, B.; Oja, A.E.; Stark, R.; Brasser, G.; Jongejan, A.; Jonkers, R.E.; Nota, B.; et al. Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. Nat. Immunol. 2016, 17, 1467–1478. [Google Scholar] [CrossRef]
  42. Pan, Y.; Tian, T.; Park, C.O.; Lofftus, S.Y.; Mei, S.; Liu, X.; Luo, C.; O’Malley, J.T.; Gehad, A.; Teague, J.E.; et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 2017, 543, 252–256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Liikanen, I.; Lauhan, C.; Quon, S.; Omilusik, K.; Phan, A.T.; Bartrolí, L.B.; Ferry, A.; Goulding, J.; Chen, J.; Scott-Browne, J.P.; et al. Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells. J. Clin. Investig. 2021, 131, e143729. [Google Scholar] [CrossRef]
  44. Mackay, L.K.; Wynne-Jones, E.; Freestone, D.; Pellicci, D.G.; Mielke, L.A.; Newman, D.M.; Braun, A.; Masson, F.; Kallies, A.; Belz, G.T.; et al. T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate. Immunity 2015, 43, 1101–1111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Mackay, L.K.; Minnich, M.; Kragten, N.A.M.; Liao, Y.; Nota, B.; Seillet, C.; Zaid, A.; Man, K.; Preston, S.; Freestone, D.; et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 2016, 352, 459–463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Strobl, J.; Pandey, R.V.; Krausgruber, T.; Bayer, N.; Kleissl, L.; Reininger, B.; Vieyra-Garcia, P.; Wolf, P.; Jentus, M.-M.; Mitterbauer, M.; et al. Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease (GVHD). Sci. Transl. Med. 2020, 12, eabb7028. [Google Scholar] [CrossRef] [PubMed]
  47. Milner, J.J.; Toma, C.; Yu, B.; Zhang, K.; Omilusik, K.; Phan, A.T.; Wang, D.; Getzler, A.J.; Nguyen, T.; Crotty, S.; et al. Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 2017, 552, 253–257. [Google Scholar] [CrossRef]
  48. Campbell, J.J.; Haraldsen, G.; Pan, J.; Rottman, J.; Qin, S.; Ponath, P.; Andrew, D.P.; Warnke, R.; Ruffing, N.; Kassam, N.; et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 1999, 400, 776–780. [Google Scholar] [CrossRef]
  49. Homey, B.; Alenius, H.; Müller, A.; Soto, H.; Bowman, E.P.; Yuan, W.; McEvoy, L.; Lauerma, A.I.; Assmann, T.; Bünemann, E.; et al. CCL27–CCR10 interactions regulate T cell–mediated skin inflammation. Nat. Med. 2002, 8, 157–165. [Google Scholar] [CrossRef]
  50. McCully, M.L.; Ladell, K.; Hakobyan, S.; Mansel, R.E.; Price, D.A.; Moser, B. Epidermis instructs skin homing receptor expression in human T cells. Blood 2012, 120, 4591–4598. [Google Scholar] [CrossRef] [Green Version]
  51. Xia, M.; Hu, S.; Fu, Y.; Jin, W.; Yi, Q.; Matsui, Y.; Yang, J.; McDowell, M.A.; Sarkar, S.; Kalia, V.; et al. CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in the skin. J. Allergy Clin. Immunol. 2014, 134, 634–644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Zaid, A.; Hor, J.L.; Christo, S.N.; Groom, J.R.; Heath, W.R.; Mackay, L.K.; Mueller, S.N. Chemokine Receptor–Dependent Control of Skin Tissue–Resident Memory T Cell Formation. J. Immunol. 2017, 199, 2451–2459. [Google Scholar] [CrossRef] [Green Version]
  53. Kok, L.; Dijkgraaf, F.E.; Urbanus, J.; Bresser, K.; Vredevoogd, D.W.; Cardoso, R.F.; Perié, L.; Beltman, J.B.; Schumacher, T.N. A committed tissue-resident memory T cell precursor within the circulating CD8+ effector T cell pool. J. Exp. Med. 2020, 217, e20191711. [Google Scholar] [CrossRef]
  54. Kurd, N.S.; He, Z.; Louis, T.L.; Milner, J.J.; Omilusik, K.D.; Jin, W.; Tsai, M.S.; Widjaja, C.E.; Kanbar, J.N.; Olvera, J.G.; et al. Early precursors and molecular determinants of tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing. Sci. Immunol. 2020, 5, eaaz6894. [Google Scholar] [CrossRef]
  55. Sathaliyawala, T.; Kubota, M.; Yudanin, N.; Turner, D.; Camp, P.; Thome, J.J.C.; Bickham, K.L.; Lerner, H.; Goldstein, M.; Sykes, M.; et al. Distribution and Compartmentalization of Human Circulating and Tissue-Resident Memory T Cell Subsets. Immunity 2013, 38, 187–197. [Google Scholar] [CrossRef] [Green Version]
  56. Kumar, B.V.; Ma, W.; Miron, M.; Granot, T.; Guyer, R.S.; Carpenter, D.J.; Senda, T.; Sun, X.; Ho, S.-H.; Lerner, H.; et al. Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. Cell Rep. 2017, 20, 2921–2934. [Google Scholar] [CrossRef] [Green Version]
  57. Wong, M.T.; Ong, D.E.H.; Lim, F.S.H.; Teng, K.W.W.; McGovern, N.; Narayanan, S.; Ho, W.Q.; Cerny, D.; Tan, H.K.K.; Anicete, R.; et al. A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures. Immunity 2016, 45, 442–456. [Google Scholar] [CrossRef] [Green Version]
  58. Clark, R.A.; Watanabe, R.; Teague, J.E.; Schlapbach, C.; Tawa, M.C.; Adams, N.; Dorosario, A.A.; Chaney, K.S.; Cutler, C.S.; LeBoeuf, N.R.; et al. Skin Effector Memory T Cells Do Not Recirculate and Provide Immune Protection in Alemtuzumab-Treated CTCL Patients. Sci. Transl. Med. 2012, 4, 117ra7. [Google Scholar] [CrossRef] [Green Version]
  59. Koguchi-Yoshioka, H.; Hoffer, E.; Cheuk, S.; Matsumura, Y.; Vo, S.; Kjellman, P.; Grema, L.; Ishitsuka, Y.; Nakamura, Y.; Okiyama, N.; et al. Skin T cells maintain their diversity and functionality in the elderly. Commun. Biol. 2021, 4, 13. [Google Scholar] [CrossRef]
  60. Park, C.O.; Fu, X.; Jiang, X.; Pan, Y.; Teague, J.E.; Collins, N.; Tian, T.; O’Malley, J.T.; Emerson, R.O.; Kim, J.H.; et al. Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection. J. Allergy Clin. Immunol. 2018, 142, 647–662. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Collins, N.; Jiang, X.; Zaid, A.; Macleod, B.L.; Li, J.; Park, C.O.; Haque, A.; Bedoui, S.; Heath, W.R.; Mueller, S.N.; et al. Skin CD4+ memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat. Commun. 2016, 7, 11514. [Google Scholar] [CrossRef] [PubMed]
  62. Cheuk, S.; Wikén, M.; Blomqvist, L.; Nylén, S.; Talme, T.; Ståhle, M.; Eidsmo, L. Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis. J. Immunol. 2014, 192, 3111–3120. [Google Scholar] [CrossRef] [Green Version]
  63. Adachi, T.; Kobayashi, T.; Sugihara, E.; Yamada, T.; Ikuta, K.; Pittaluga, S.; Saya, H.; Amagai, M.; Nagao, K. Hair follicle–derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat. Med. 2015, 21, 1272–1279. [Google Scholar] [CrossRef] [PubMed]
  64. Tokura, Y.; Phadungsaksawasdi, P.; Kurihara, K.; Fujiyama, T.; Honda, T. Pathophysiology of Skin Resident Memory T Cells. Front. Immunol. 2021, 11, 3789. [Google Scholar] [CrossRef] [PubMed]
  65. Adams, E.J.; Gu, S.; Luoma, A.M. Human gamma delta T cells: Evolution and ligand recognition. Cell. Immunol. 2015, 296, 31–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Reitermaier, R.; Krausgruber, T.; Fortelny, N.; Ayub, T.; Vieyra-Garcia, P.A.; Kienzl, P.; Wolf, P.; Scharrer, A.; Fiala, C.; Kölz, M.; et al. αβγδ T cells play a vital role in fetal human skin development and immunity. J. Exp. Med. 2021, 218, e20201189. [Google Scholar] [CrossRef]
  67. Koguchi-Yoshioka, H.; Watanabe, R.; Matsumura, Y.; Okiyama, N.; Ishitsuka, Y.; Nakamura, Y.; Fujisawa, Y.; Fujimoto, M. The Possible Linkage of Granzyme B-Producing Skin T Cells with the Disease Prognosis of Alopecia Areata. J. Investig. Dermatol. 2021, 141, 427–429. [Google Scholar] [CrossRef] [PubMed]
  68. Kim, S.; Park, C.; Shin, J.; Noh, J.; Kim, H.; Kim, J.; Lee, H.; Lee, J.; Kupper, T.S.; Lee, K. Multicytokine-producing tissue resident memory (TRM) cells in atopic dermatitis patient. J. Investig. Dermatol. 2016, 136, S9. [Google Scholar] [CrossRef]
  69. Boniface, K.; Jacquemin, C.; Darrigade, A.-S.; Dessarthe, B.; Martins, C.; Boukhedouni, N.; Vernisse, C.; Grasseau, A.; Thiolat, D.; Rambert, J.; et al. Vitiligo Skin Is Imprinted with Resident Memory CD8 T Cells Expressing CXCR3. J. Investig. Dermatol. 2018, 138, 355–364. [Google Scholar] [CrossRef] [Green Version]
  70. Han, J.; Zhao, Y.; Shirai, K.; Molodtsov, A.; Kolling, F.W.; Fisher, J.L.; Zhang, P.; Yan, S.; Searles, T.G.; Bader, J.M.; et al. Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy. Nat. Cancer 2021, 2, 300–311. [Google Scholar] [CrossRef]
  71. Zeng, J.; Luo, S.; Huang, Y.; Lu, Q. Critical role of environmental factors in the pathogenesis of psoriasis. J. Dermatol. 2017, 44, 863–872. [Google Scholar] [CrossRef] [Green Version]
  72. Li, Q.; Chandran, V.; Tsoi, L.; O’Rielly, D.; Nair, R.P.; Gladman, D.; Elder, J.T.; Rahman, P. Quantifying Differences in Heritability among Psoriatic Arthritis (PsA), Cutaneous Psoriasis (PsC) and Psoriasis vulgaris (PsV). Sci. Rep. 2020, 10, 4925. [Google Scholar] [CrossRef] [Green Version]
  73. Lande, R.; Botti, E.; Jandus, C.; Dojcinovic, D.; Fanelli, G.; Conrad, C.; Chamilos, G.; Feldmeyer, L.; Marinari, B.; Chon, S.; et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat. Commun. 2014, 5, 5621. [Google Scholar] [CrossRef]
  74. Bhushan, M.; Bleiker, T.O.; Ballsdon, A.E.; Allen, M.H.; Sopwith, M.; Robinson, M.K.; Clarke, C.; Weller, R.P.J.B.; Graham-Brown, R.A.C.; Keefe, M.; et al. Anti-E-selectin is ineffective in the treatment of psoriasis: A randomized trial. Br. J. Dermatol. 2002, 146, 824–831. [Google Scholar] [CrossRef]
  75. Lebwohl, M.; Tyring, S.K.; Hamilton, T.K.; Toth, D.; Glazer, S.; Tawfik, N.H.; Walicke, P.; Dummer, W.; Wang, X.; Garovoy, M.R.; et al. A Novel Targeted T-Cell Modulator, Efalizumab, for Plaque Psoriasis. N. Engl. J. Med. 2003, 349, 2004–2013. [Google Scholar] [CrossRef] [Green Version]
  76. Conrad, C.; Boyman, O.; Tonel, G.; Tun-Kyi, A.; Laggner, U.; de Fougerolles, A.; Kotelianski, V.; Gardner, H.; Nestle, F.O. α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat. Med. 2007, 13, 836–842. [Google Scholar] [CrossRef] [PubMed]
  77. Gallais Sérézal, I.; Hoffer, E.; Ignatov, B.; Martini, E.; Zitti, B.; Ehrström, M.; Eidsmo, L. A skewed pool of resident T cells triggers psoriasis-associated tissue responses in never-lesional skin from patients with psoriasis. J. Allergy Clin. Immunol. 2019, 143, 1444–1454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Nograles, K.E.; Zaba, L.C.; Guttman-Yassky, E.; Fuentes-Duculan, J.; Suárez-Fariñas, M.; Cardinale, I.; Khatcherian, A.; Gonzalez, J.; Pierson, K.C.; White, T.R.; et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br. J. Dermatol. 2008, 159, 1092–1102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Martini, E.; Wikén, M.; Cheuk, S.; Gallais Sérézal, I.; Baharom, F.; Ståhle, M.; Smed-Sörensen, A.; Eidsmo, L. Dynamic Changes in Resident and Infiltrating Epidermal Dendritic Cells in Active and Resolved Psoriasis. J. Investig. Dermatol. 2017, 137, 865–873. [Google Scholar] [CrossRef] [Green Version]
  80. Matos, T.R.; O’Malley, J.T.; Lowry, E.L.; Hamm, D.; Kirsch, I.R.; Robins, H.S.; Kupper, T.S.; Krueger, J.G.; Clark, R.A. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17–producing αβ T cell clones. J. Clin. Investig. 2017, 127, 4031–4041. [Google Scholar] [CrossRef] [Green Version]
  81. Lande, R.; Gregorio, J.; Facchinetti, V.; Chatterjee, B.; Wang, Y.-H.; Homey, B.; Cao, W.; Wang, Y.-H.; Su, B.; Nestle, F.O.; et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007, 449, 564–569. [Google Scholar] [CrossRef] [PubMed]
  82. Zaba, L.C.; Krueger, J.G.; Lowes, M.A. Resident and “Inflammatory” Dendritic Cells in Human Skin. J. Investig. Dermatol. 2009, 129, 302–308. [Google Scholar] [CrossRef] [Green Version]
  83. Arakawa, A.; Siewert, K.; Stöhr, J.; Besgen, P.; Kim, S.-M.; Rühl, G.; Nickel, J.; Vollmer, S.; Thomas, P.; Krebs, S.; et al. Melanocyte antigen triggers autoimmunity in human psoriasis. J. Exp. Med. 2015, 212, 2203–2212. [Google Scholar] [CrossRef]
  84. Cheung, K.L.; Jarrett, R.; Subramaniam, S.; Salimi, M.; Gutowska-Owsiak, D.; Chen, Y.-L.; Hardman, C.; Xue, L.; Cerundolo, V.; Ogg, G. Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a. J. Exp. Med. 2016, 213, 2399–2412. [Google Scholar] [CrossRef] [Green Version]
  85. Jin, L.; Wang, G. Keratin 17: A Critical Player in the Pathogenesis of Psoriasis. Med. Res. Rev. 2014, 34, 438–454. [Google Scholar] [CrossRef]
  86. Johnston, A.; Gudjonsson, J.E.; Sigmundsdottir, H.; Love, T.J.; Valdimarsson, H. Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8+ T cells. Clin. Exp. Immunol. 2004, 138, 83–93. [Google Scholar] [CrossRef]
  87. Kurihara, K.; Fujiyama, T.; Phadungsaksawasdi, P.; Ito, T.; Tokura, Y. Significance of IL-17A-producing CD8+CD103+ skin resident memory T cells in psoriasis lesion and their possible relationship to clinical course. J. Dermatol. Sci. 2019, 95, 21–27. [Google Scholar] [CrossRef] [PubMed]
  88. Vo, S.; Watanabe, R.; Koguchi-Yoshioka, H.; Matsumura, Y.; Ishitsuka, Y.; Nakamura, Y.; Okiyama, N.; Fujisawa, Y.; Fujimoto, M. CD8 resident memory T cells with interleukin 17A-producing potential are accumulated in disease-naïve nonlesional sites of psoriasis possibly in correlation with disease duration. Br. J. Dermatol. 2019, 181, 410–412. [Google Scholar] [CrossRef]
  89. Fenix, K.; Wijesundara, D.K.; Cowin, A.J.; Grubor-Bauk, B.; Kopecki, Z. Immunological memory in imiquimod-induced murine model of psoriasiform dermatitis. Int. J. Mol. Sci. 2020, 21, 7228. [Google Scholar] [CrossRef] [PubMed]
  90. Di Meglio, P.; Villanova, F.; Navarini, A.A.; Mylonas, A.; Tosi, I.; Nestle, F.O.; Conrad, C. Targeting CD8+ T cells prevents psoriasis development. J. Allergy Clin. Immunol. 2016, 138, 274–276.e6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Fujiyama, T.; Umayahara, T.; Kurihara, K.; Shimauchi, T.; Ito, T.; Aoshima, M.; Otobe, E.; Hashizume, H.; Yagi, H.; Tokura, Y. Skin infiltration of pathogenic migratory and resident T cells is decreased by Secukinumab treatment in psoriasis. J. Investig. Dermatol. 2020, 140, 2073–2076. [Google Scholar] [CrossRef]
  92. Mashiko, S.; Edelmayer, R.M.; Bi, Y.; Olson, L.M.; Wetter, J.B.; Wang, J.; Maari, C.; Saint-Cyr Proulx, E.; Kaimal, V.; Li, X.; et al. Persistence of Inflammatory Phenotype in Residual Psoriatic Plaques in Patients on Effective Biologic Therapy. J. Investig. Dermatol. 2020, 140, 1015–1025.e4. [Google Scholar] [CrossRef]
  93. Gallais Sérézal, I.; Classon, C.; Cheuk, S.; Barrientos-Somarribas, M.; Wadman, E.; Martini, E.; Chang, D.; Xu Landén, N.; Ehrström, M.; Nylén, S.; et al. Resident T Cells in Resolved Psoriasis Steer Tissue Responses that Stratify Clinical Outcome. J. Investig. Dermatol. 2018, 138, 1754–1763. [Google Scholar] [CrossRef] [Green Version]
  94. Papp, K.A.; Reich, K.; Paul, C.; Blauvelt, A.; Baran, W.; Bolduc, C.; Toth, D.; Langley, R.G.; Cather, J.; Gottlieb, A.B.; et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br. J. Dermatol. 2016, 175, 273–286. [Google Scholar] [CrossRef]
  95. Mehta, H.; Mashiko, S.; Angsana, J.; Rubio, M.; Hsieh, Y.-C.M.; Maari, C.; Reich, K.; Blauvelt, A.; Bissonnette, R.; Muñoz-Elías, E.J.; et al. Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab. J. Investig. Dermatol. 2021, 141, 1707–1718.e9. [Google Scholar] [CrossRef] [PubMed]
  96. Søyland, E.; Heier, I.; Rodríguez-Gallego, C.; Mollnes, T.E.; Johansen, F.-E.; Holven, K.B.; Halvorsen, B.; Aukrust, P.; Jahnsen, F.L.; de la Rosa Carrillo, D.; et al. Sun exposure induces rapid immunological changes in skin and peripheral blood in patients with psoriasis. Br. J. Dermatol. 2011, 164, 344–355. [Google Scholar] [CrossRef]
  97. Dyring-Andersen, B.; Bonefeld, C.M.; Bzorek, M.; Løvendorf, M.B.; Lauritsen, J.P.H.; Skov, L.; Geisler, C. The Vitamin D Analogue Calcipotriol Reduces the Frequency of CD8+IL-17+ T Cells in Psoriasis Lesions. Scand. J. Immunol. 2015, 82, 84–91. [Google Scholar] [CrossRef]
  98. Fujiyama, T.; Ito, T.; Umayahara, T.; Ikeya, S.; Tatsuno, K.; Funakoshi, A.; Hashizume, H.; Tokura, Y. Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion. J. Allergy Clin. Immunol. 2016, 138, 517–528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Gottlieb, S.L.; Hayes, E.; Gilleaudeau, P.; Cardinale, I.; Gottlieb, A.B.; Krueger, J.G. Cellular actions of etretinate in psoriasis: Enhanced epidermal differentiation and reduced cell-mediated inflammation are unexpected outcomes. J. Cutan. Pathol. 1996, 23, 404–418. [Google Scholar] [CrossRef]
  100. Xiao, S.; Jin, H.; Korn, T.; Liu, S.M.; Oukka, M.; Lim, B.; Kuchroo, V.K. Retinoic Acid Increases Foxp3+ Regulatory T Cells and Inhibits Development of Th17 Cells by Enhancing TGF-β-Driven Smad3 Signaling and Inhibiting IL-6 and IL-23 Receptor Expression. J. Immunol. 2008, 181, 2277–2284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Gottlieb, A.B.; Matheson, R.T.; Menter, A.; Leonardi, C.L.; Day, R.M.; Hu, C.; Schafer, P.H. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: A phase II open-label study. J. Drugs Dermatol. 2013, 12, 888–897. [Google Scholar] [PubMed]
  102. Robbins, K.; Bissonnette, R.; Maeda-Chubachi, T.; Ye, L.; Peppers, J.; Gallagher, K.; Kraus, J.E. Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis. J. Am. Acad. Dermatol. 2019, 80, 714–721. [Google Scholar] [CrossRef] [PubMed]
  103. Kobayashi, T.; Ricardo-Gonzalez, R.R.; Moro, K. Skin-Resident Innate Lymphoid Cells—Cutaneous Innate Guardians and Regulators. Trends Immunol. 2020, 41, 100–112. [Google Scholar] [CrossRef] [PubMed]
  104. Weisel, N.M.; Weisel, F.J.; Farber, D.L.; Borghesi, L.A.; Shen, Y.; Ma, W.; Luning Prak, E.T.; Shlomchik, M.J. Comprehensive analyses of B-cell compartments across the human body reveal novel subsets and a gut-resident memory phenotype. Blood 2020, 136, 2774–2785. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. A. Surface markers, intracellular molecules, and transcription factors of TRM. The expression levels of these molecules on TRM are shown by upward arrows (increased expressions) and downward arrows (decreased expressions). Created with BioRender.com (accessed on 21 August 2021).
Figure 1. A. Surface markers, intracellular molecules, and transcription factors of TRM. The expression levels of these molecules on TRM are shown by upward arrows (increased expressions) and downward arrows (decreased expressions). Created with BioRender.com (accessed on 21 August 2021).
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Figure 2. Development of TRM in psoriasis. TRM are activated by either autoantigens or cytokines/chemokines. Autoantigens include ADMTSL5 on the surface of melanocytes, PLAG4D from mast cells and keratinocytes, and keratin 17 from keratinocytes. Antimicrobial peptide LL-37, also from keratinocytes, binds to self-DNA to activate pDC and TIP-DC, leading to the production of IL-23/TNF-α. IL-23/15 from Langerhans cells and CCL20 from keratinocytes also activate TRM. These stimulated TRM produce proinflammatory cytokines, such as IL-17A and IL-22, the hallmarks of psoriasis. The development of pathogenic TRM can be inhibited by stopping pathways related to TRM activation or directly inhibiting the activity of TRM (red inhibition icon). Created with BioRender.com (assessed on 21 August 2021).
Figure 2. Development of TRM in psoriasis. TRM are activated by either autoantigens or cytokines/chemokines. Autoantigens include ADMTSL5 on the surface of melanocytes, PLAG4D from mast cells and keratinocytes, and keratin 17 from keratinocytes. Antimicrobial peptide LL-37, also from keratinocytes, binds to self-DNA to activate pDC and TIP-DC, leading to the production of IL-23/TNF-α. IL-23/15 from Langerhans cells and CCL20 from keratinocytes also activate TRM. These stimulated TRM produce proinflammatory cytokines, such as IL-17A and IL-22, the hallmarks of psoriasis. The development of pathogenic TRM can be inhibited by stopping pathways related to TRM activation or directly inhibiting the activity of TRM (red inhibition icon). Created with BioRender.com (assessed on 21 August 2021).
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Vu, T.T.; Koguchi-Yoshioka, H.; Watanabe, R. Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis. J. Clin. Med. 2021, 10, 3822. https://doi.org/10.3390/jcm10173822

AMA Style

Vu TT, Koguchi-Yoshioka H, Watanabe R. Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis. Journal of Clinical Medicine. 2021; 10(17):3822. https://doi.org/10.3390/jcm10173822

Chicago/Turabian Style

Vu, Trung T., Hanako Koguchi-Yoshioka, and Rei Watanabe. 2021. "Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis" Journal of Clinical Medicine 10, no. 17: 3822. https://doi.org/10.3390/jcm10173822

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