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  • Review Article
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Cutaneous T cell immunity

Nature Immunology volume 26, pages 1014–1022 (2025)Cite this article

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Abstract

The skin is the primary barrier against environmental insults, safeguarding the body from mechanical, chemical and pathogenic threats. The frequent exposure of the skin to environmental challenges requires an immune response that incorporates a sophisticated combination of defenses. Tissue-resident lymphocytes are pivotal for skin immunity, working in tandem with commensal bacteria to maintain immune surveillance and homeostasis, as well as participating in the pathogenesis of several skin diseases. Indeed, it has been estimated that the human skin harbors nearly twice as many T cells as found in the circulation. Effective treatment of skin diseases and new therapy development require a thorough understanding of the complex interactions among skin tissue, immune cells and the microbiota, which together regulate the skin’s immune balance. This Review explores the latest developments and understanding of this critical barrier organ, with a specific focus on the role of skin-resident T cells.

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Fig. 1: Skin anatomy and immune cell composition.
Fig. 2: Comparative insights between mouse and human skin.
Fig. 3: Distinct therapeutic approaches to TRM cell-mediated autoimmune diseases.

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References

  1. Pasparakis, M., Haase, I. & Nestle, F. O. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289–301 (2014).

    CAS  PubMed  Google Scholar 

  2. Nestle, F. O., Di Meglio, P., Qin, J.-Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679–691 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Proksch, E., Brandner, J. M. & Jensen, J.-M. The skin: an indispensable barrier. Exp. Dermatol. 17, 1063–1072 (2008).

    PubMed  Google Scholar 

  4. Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. 4, 211–222 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gudjonsson, J. E., Johnston, A., Dyson, M., Valdimarsson, H. & Elder, J. T. Mouse models of psoriasis. J. Invest. Dermatol. 127, 1292–1308 (2007).

    CAS  PubMed  Google Scholar 

  6. Watanabe, R. et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci. Transl. Med. 7, 279ra39 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. Elias, P. M. et al. Origin of the corneocyte lipid envelope (CLE): observations in harlequin ichthyosis and cultured human keratinocytes. J. Invest. Dermatol. 115, 765–769 (2000).

    CAS  PubMed  Google Scholar 

  8. Elias, P. M. Stratum corneum defensive functions: an integrated view. J. Invest. Dermatol. 125, 183–200 (2005).

    CAS  PubMed  Google Scholar 

  9. Simmons, J. & Gallo, R. L. The central roles of keratinocytes in coordinating skin immunity. J. Invest. Dermatol. 144, 2377–2398 (2024).

    CAS  PubMed  Google Scholar 

  10. Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nat. Rev. Immunol. 12, 503–516 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Köck, A. et al. Human keratinocytes are a source for tumor necrosis factor α: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J. Exp. Med. 172, 1609–1614 (1990).

    PubMed  Google Scholar 

  12. Wang, G. et al. Bacteria induce skin regeneration via IL-1β signaling. Cell Host Microbe 29, 777–791 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gober, M. D., Fishelevich, R., Zhao, Y., Unutmaz, D. & Gaspari, A. A. Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis. J. Invest. Dermatol. 128, 1460–1469 (2008).

    CAS  PubMed  Google Scholar 

  15. Constantinides, M. G. et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science 366, eaax6624 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sun, Z. et al. Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis. J. Allergy Clin. Immunol. 147, 1764–1777 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kobayashi, T., Ricardo-Gonzalez, R. R. & Moro, K. Skin-resident innate lymphoid cells—cutaneous innate guardians and regulators. Trends Immunol. 41, 100–112 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Filtjens, J. et al. Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection. Nat. Commun. 12, 2936 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang, S. et al. Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis. Cell 184, 2151–2166 (2021).

    CAS  PubMed  Google Scholar 

  21. Deng, L., Gillis, J. E., Chiu, I. M. & Kaplan, D. H. Sensory neurons: an integrated component of innate immunity. Immunity 57, 815–831 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Adachi, T. et al. Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat. Med. 21, 1272–1279 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ali, N. & Rosenblum, M. D. Regulatory T cells in skin. Immunology 152, 372–381 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cohen, J. N. et al. Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche. Sci. Immunol. 9, eadh0152 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Makrantonaki, E., Ganceviciene, R. & Zouboulis, C. An update on the role of the sebaceous gland in the pathogenesis of acne. Dermato-Endocrinology 3, 41–49 (2011).

    PubMed  PubMed Central  Google Scholar 

  27. Gallo, R. L. & Nakatsuji, T. Microbial symbiosis with the innate immune defense system of the skin. J. Invest. Dermatol. 131, 1974–1980 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shu, M. et al. Fermentation of Propionibacterium acnes, a commensal bacterium in the human skin microbiome, as skin probiotics against methicillin-resistant Staphylococcus aureus. PLoS ONE 8, e55380 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190–1192 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu, G. et al. Genus-wide comparative genomics of Malassezia delineates its phylogeny, physiology, and niche adaptation on human skin. PLoS Genet. 11, e1005614 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. Schittek, B. et al. Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nat. Immunol. 2, 1133–1137 (2001).

    CAS  PubMed  Google Scholar 

  32. Dawson, T. L. Jr. Malassezia globosa and restricta: breakthrough understanding of the etiology and treatment of dandruff and seborrheic dermatitis through whole-genome analysis. J. Investig. Dermatol. Symp. Proc. 12, 15–19 (2007).

    CAS  PubMed  Google Scholar 

  33. Stoitzner, P. et al. Langerhans cells cross-present antigen derived from skin. Proc. Natl Acad. Sci. USA 103, 7783–7788 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Klechevsky, E. et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497–510 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kaplan, D. H. Ontogeny and function of murine epidermal Langerhans cells. Nat. Immunol. 18, 1068–1075 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kashem, S. W., Haniffa, M. & Kaplan, D. H. Antigen-presenting cells in the skin. Annu. Rev. Immunol. 35, 469–499 (2017).

    CAS  PubMed  Google Scholar 

  37. Gordon, S., Plüddemann, A. & Martinez Estrada, F. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol. Rev. 262, 36–55 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Eberl, G., Colonna, M., Di Santo, J. P. & McKenzie, A. N. J. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science 348, aaa6566 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat. Immunol. 14, 564–573 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Weizman, O.-E. et al. ILC1 confer early host protection at initial sites of viral infection. Cell 171, 795–808 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zaric, M. et al. Skin immunisation activates an innate lymphoid cell–monocyte axis regulating CD8+ effector recruitment to mucosal tissues. Nat. Commun. 10, 2214 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. Gladiator, A., Wangler, N., Trautwein-Weidner, K. & LeibundGut-Landmann, S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521–525 (2013).

    CAS  PubMed  Google Scholar 

  43. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Torcellan, T. et al. Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection. Immunity 57, 124–140 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Shibuya, R. & Kim, B. S. Skin-homing basophils and beyond. Front. Immunol. 13, 1059098 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kawakami, T., Ando, T., Kimura, M., Wilson, B. S. & Kawakami, Y. Mast cells in atopic dermatitis. Curr. Opin. Immunol. 21, 666–678 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Siracusa, M. C., Kim, B. S., Spergel, J. M. & Artis, D. Basophils and allergic inflammation. J. Allergy Clin. Immunol. 132, 789–801 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Dudeck, A. et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34, 973–984 (2011).

    CAS  PubMed  Google Scholar 

  49. Clark, R. A. Resident memory T cells in human health and disease. Sci. Transl. Med. 7, 269rv1 (2015).

    PubMed  PubMed Central  Google Scholar 

  50. Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).

    CAS  PubMed  Google Scholar 

  51. Christo, S. N., Park, S. L., Mueller, S. N. & Mackay, L. K. The multifaceted role of tissue-resident memory T cells. Annu. Rev. Immunol. 42, 317–345 (2024).

    CAS  PubMed  Google Scholar 

  52. Hirai, T. et al. Keratinocyte-mediated activation of the cytokine TGF-β maintains skin recirculating memory CD8+ T cells. Immunity 50, 1249–1261 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Klicznik, M. M. et al. Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci. Immunol. 4, eaav8995 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Strobl, J. et al. Human resident memory T cells exit the skin and mediate systemic Th2-driven inflammation. J. Exp. Med. 218, e20210417 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl. Med. 4, 117ra7 (2012).

    PubMed  PubMed Central  Google Scholar 

  56. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).

    CAS  PubMed  Google Scholar 

  57. Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-α. J. Exp. Med. 199, 731–736 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Mackay, L. K. et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).

    CAS  PubMed  Google Scholar 

  59. Sharp, L. L., Jameson, J. M., Cauvi, G. & Havran, W. L. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat. Immunol. 6, 73–79 (2005).

    CAS  PubMed  Google Scholar 

  60. Jameson, J. et al. A role for skin γδ T cells in wound repair. Science 296, 747–749 (2002).

    CAS  PubMed  Google Scholar 

  61. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Crawford, G. et al. Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response. Nat. Immunol. 19, 859–870 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Park, C. O. 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. 142, 647–662 (2018).

    CAS  PubMed  Google Scholar 

  64. Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Davies, B. et al. Cutting edge: tissue-resident memory T cells generated by multiple immunizations or localized deposition provide enhanced immunity. J. Immunol. 198, 2233–2237 (2017).

    CAS  PubMed  Google Scholar 

  67. Trubiano, J. A. et al. Analysis of skin-resident memory T cells following drug hypersensitivity reactions. J. Invest. Dermatol. 140, 1442–1445 (2020).

    CAS  PubMed  Google Scholar 

  68. Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Dijkgraaf, F. E. et al. Tissue patrol by resident memory CD8+ T cells in human skin. Nat. Immunol. 20, 756–764 (2019).

    CAS  PubMed  Google Scholar 

  71. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

    CAS  PubMed  Google Scholar 

  72. Collins, N. et al. Skin CD4+ memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat. Commun. 7, 11514 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bos, J. D. et al. The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin. J. Invest. Dermatol. 88, 569–573 (1987).

    CAS  PubMed  Google Scholar 

  74. Hirai, T., Whitley, S. K. & Kaplan, D. H. Migration and function of memory CD8+ T cells in skin. J. Invest. Dermatol. 140, 748–755 (2020).

    CAS  PubMed  Google Scholar 

  75. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhu, J. et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595–603 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Szabo, P. A., Miron, M. & Farber, D. L. Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 4, eaas9673 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gray, J. I. & Farber, D. L. Tissue-resident immune cells in humans. Annu. Rev. Immunol. 40, 195–220 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Qu, G. et al. Comparing mouse and human tissue-resident γδ T cells. Front. Immunol. 13, 891687 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

    CAS  PubMed  Google Scholar 

  81. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kok, L. et al. A committed tissue-resident memory T cell precursor within the circulating CD8+ effector T cell pool. J. Exp. Med. 217, e20191711 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Poon, M. M. L. et al. Tissue adaptation and clonal segregation of human memory T cells in barrier sites. Nat. Immunol. 24, 309–319 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

    CAS  PubMed  Google Scholar 

  85. Szabo, P. A. et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat. Commun. 10, 4706 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Obers, A. et al. Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency. Immunity 57, 2615–2633 (2024).

    CAS  PubMed  Google Scholar 

  87. Buquicchio, F. A. et al. Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation. Immunity 57, 2202–2215 (2024).

    CAS  PubMed  Google Scholar 

  88. Cepek, K. L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372, 190–193 (1994).

    CAS  PubMed  Google Scholar 

  89. Fonseca, R. et al. Runx3 drives a CD8+ T cell tissue residency program that is absent in CD4+ T cells. Nat. Immunol. 23, 1236–1245 (2022).

    CAS  PubMed  Google Scholar 

  90. Cheuk, S. et al. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J. Immunol. 192, 3111–3120 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Park, S. L. et al. Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells. Science 382, 1073–1079 (2023).

    CAS  PubMed  Google Scholar 

  92. Glennie, N. D. et al. Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection. J. Exp. Med. 212, 1405–1414 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cheuk, S. et al. CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity 46, 287–300 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).

    CAS  PubMed  Google Scholar 

  95. Khan, T. N., Mooster, J. L., Kilgore, A. M., Osborn, J. F. & Nolz, J. C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J. Exp. Med. 213, 951–966 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Hirai, T. et al. Competition for active TGFβ cytokine allows for selective retention of antigen-specific tissue-resident memory T cells in the epidermal niche. Immunity 54, 84–98 (2021).

    CAS  PubMed  Google Scholar 

  97. Fonseca, R. et al. Developmental plasticity allows outside–in immune responses by resident memory T cells. Nat. Immunol. 21, 412–421 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Christo, S. N. et al. Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity. Nat. Immunol. 22, 1140–1151 (2021).

    CAS  PubMed  Google Scholar 

  99. Bromley, S. K., Yan, S., Tomura, M., Kanagawa, O. & Luster, A. D. Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J. Immunol. 190, 970–976 (2013).

    CAS  PubMed  Google Scholar 

  100. Glennie, N. D., Volk, S. W. & Scott, P. Skin-resident CD4+ T cells protect against Leishmania major by recruiting and activating inflammatory monocytes. PLoS Pathog. 13, e1006349 (2017).

    PubMed  PubMed Central  Google Scholar 

  101. Schenkel, J. M., Fraser, K. A., Vezys, V. & Masopust, D. Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 14, 509–513 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Schenkel, J. M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Ariotti, S. et al. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014).

    CAS  PubMed  Google Scholar 

  104. Park, S. L., Gebhardt, T. & Mackay, L. K. Tissue-resident memory T cells in cancer immunosurveillance. Trends Immunol. 40, 735–747 (2019).

    CAS  PubMed  Google Scholar 

  105. Malik, B. T. et al. Resident memory T cells in the skin mediate durable immunity to melanoma. Sci. Immunol. 2, eaam6346 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. Park, S. L. et al. Tissue-resident memory CD8+ T cells promote melanoma–immune equilibrium in skin. Nature 565, 366–371 (2019).

    CAS  PubMed  Google Scholar 

  107. Edwards, J. 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. 24, 3036–3045 (2018).

    CAS  PubMed  Google Scholar 

  108. Murray, T. et al. Very late antigen-1 marks functional tumor-resident CD8 T cells and correlates with survival of melanoma patients. Front. Immunol. 7, 573 (2016).

    PubMed  PubMed Central  Google Scholar 

  109. Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Djenidi, F. et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J. Immunol. 194, 3475–3486 (2015).

    CAS  PubMed  Google Scholar 

  111. Geisler, A. N. et al. Immune checkpoint inhibitor-related dermatologic adverse events. J. Am. Acad. Dermatol. 83, 1255–1268 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ogg, G. S., Rod Dunbar, P., Romero, P., Chen, J. L. & Cerundolo, V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J. Exp. Med. 188, 1203–1208 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Gamradt, P. et al. Inhibitory checkpoint receptors control CD8+ resident memory T cells to prevent skin allergy. J. Allergy Clin. Immunol. 143, 2147–2157 (2019).

    CAS  PubMed  Google Scholar 

  114. Shah, P. N. et al. Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets. J. Clin. Invest. 134, e178253 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Taïeb, A. & Picardo, M. Clinical practice. Vitiligo. N. Engl. J. Med. 360, 160–169 (2009).

    PubMed  Google Scholar 

  116. Matos, T. R. et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J. Clin. Invest. 127, 4031–4041 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. Narayanasetty, N. K., Pai, V. V. & Athanikar, S. B. Annular lesions in dermatology. Indian J. Dermatol. 58, 157 (2013).

    PubMed  PubMed Central  Google Scholar 

  118. Naik, S. et al. Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Kong, H. H. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Leyden, J. J., Marples, R. R. & Kligman, A. M. Staphylococcus aureus in the lesions of atopic dermatitis. Br. J. Dermatol. 90, 525–530 (1974).

    CAS  PubMed  Google Scholar 

  122. Berghöfer, B. et al. TLR7 ligands induce higher IFN-α production in females. J. Immunol. 177, 2088–2096 (2006).

    PubMed  Google Scholar 

  123. Engler, R. J. M. et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses. Arch. Intern. Med. 168, 2405–2414 (2008).

    PubMed  Google Scholar 

  124. Yang, C. et al. Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity. Immunity 55, 1268–1283 (2022).

    CAS  PubMed  Google Scholar 

  125. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    CAS  PubMed  Google Scholar 

  126. Mohammad, I. et al. Estrogen receptor α contributes to T cell-mediated autoimmune inflammation by promoting T cell activation and proliferation. Sci. Signal. 11, eaap9415 (2018).

    PubMed  Google Scholar 

  127. Guan, X. et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature 606, 791–796 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Chi, L. et al. Sexual dimorphism in skin immunity is mediated by an androgen–ILC2–dendritic cell axis. Science 384, eadk6200 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Karagaiah, P. et al. Biologic and targeted therapeutics in vitiligo. J. Cosmet. Dermatol. 22, 64–73 (2023).

    PubMed  Google Scholar 

  130. Hawkes, J. E., Chan, T. C. & Krueger, J. G. Psoriasis pathogenesis and the development of novel targeted immune therapies. J. Allergy Clin. Immunol. 140, 645–653 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Richmond, J. M. et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci. Transl. Med. 10, eaam7710 (2018).

    PubMed  PubMed Central  Google Scholar 

  132. Whitley, S. K. et al. Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells. Sci. Immunol. 7, eabq3254 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Goedkoop, A. Y. et al. Early effects of tumour necrosis factor α blockade on skin and synovial tissue in patients with active psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 63, 769–773 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Schots, L., Soenen, R., Blanquart, B., Thomas, D. & Lambert, J. Blocking interleukin-17 in psoriasis: real-world experience from the PsoPlus cohort. J. Eur. Acad. Dermatol. Venereol. 37, 698–710 (2023).

    CAS  PubMed  Google Scholar 

  135. Fenner, F. A successful eradication campaign. Global eradication of smallpox. Rev. Infect. Dis. 4, 916–930 (1982).

    CAS  PubMed  Google Scholar 

  136. Pan, Y. et al. Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge. NPJ Vaccines 6, 1 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Brooks, J. T., Marks, P., Goldstein, R. H. & Walensky, R. P. Intradermal vaccination for monkeypox—benefits for individual and public health. N. Engl. J. Med. 387, 1151–1153 (2022).

    PubMed  Google Scholar 

  138. Gálvez-Cancino, F. et al. Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma. Oncoimmunology 7, e1442163 (2018).

    PubMed  PubMed Central  Google Scholar 

  139. Kos, S. et al. Intradermal DNA vaccination combined with dual CTLA-4 and PD-1 blockade provides robust tumor immunity in murine melanoma. PLoS ONE 14, e0217762 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Nakatsuji, T. et al. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci. Adv. 4, eaao4502 (2018).

    PubMed  PubMed Central  Google Scholar 

  141. Chen, Y. E. et al. Engineered skin bacteria induce antitumor T cell responses against melanoma. Science 380, 203–210 (2023).

    CAS  PubMed  Google Scholar 

  142. Strickley, J. D. et al. Immunity to commensal papillomaviruses protects against skin cancer. Nature 575, 519–522 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Davar, D. et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 371, 595–602 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Baruch, E. N. et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 371, 602–609 (2021).

    CAS  PubMed  Google Scholar 

  145. Holtmeier, W. et al. The TCR δ repertoire in normal human skin is restricted and distinct from the TCR δ repertoire in the peripheral blood. J. Invest. Dermatol. 116, 275–280 (2001).

    CAS  PubMed  Google Scholar 

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Author notes

  1. These authors contributed equally: Pirooz Zareie, Eric S. Weiss.

Authors and Affiliations

  1. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

    Pirooz Zareie & Laura K. Mackay

  2. Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Eric S. Weiss & Daniel H. Kaplan

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  2. Eric S. Weiss
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  4. Laura K. Mackay
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P.Z., E.S.W., D.H.K. and L.K.M. wrote and edited the manuscript.

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Zareie, P., Weiss, E.S., Kaplan, D.H. et al. Cutaneous T cell immunity. Nat Immunol 26, 1014–1022 (2025). https://doi.org/10.1038/s41590-025-02145-3

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