Focus on Inflammatory Disease

The emerging role of resident memory T cells in protective immunity and inflammatory disease

Journal name:
Nature Medicine
Year published:
Published online


Over the past decade, it has become clear that there is an important subset of memory T cells that resides in tissues—tissue-resident memory T (TRM) cells. There is an emerging understanding that TRM cells have a role in human tissue-specific immune and inflammatory diseases. Furthermore, the nature of the molecular signals that maintain TRM cells in tissues is the subject of much investigation. In addition, whereas it is logical for TRM cells to be located in barrier tissues at interfaces with the environment, these cells have also been found in brain, kidney, joint and other non-barrier tissues in humans and mice. Given the biology and behavior of these cells, it is likely that they have a role in chronic relapsing and remitting diseases of both barrier and non-barrier tissues. In this Review we discuss recent insights into the biology of TRM cells with a particular focus on their roles in disease, both proven and putative.

At a glance


  1. The generation of tissue TRM cells after infection of barrier tissues.
    Figure 1: The generation of tissue TRM cells after infection of barrier tissues.

    (a) Upon first encounter with a pathogen in a barrier tissue, dendritic cells carry antigen to draining lymph nodes and present it to naive T cells. Depending on the anatomic location of the lymph node, various trafficking molecules (indicated adjacent to vessels) are expressed on the expanding activated T cell population, and effector T cells with specific tissue-homing properties preferentially exit blood in peripheral tissues. Gut-draining lymph nodes induce the expression of gut-homing molecules on antigen-activated T cells, and skin-draining lymph nodes induce the expression of skin-homing molecules on antigen-activated T cells. Analogous processes, albeit less well characterized, occur in lymph nodes draining lung and reproductive mucosa. VLA-1, very late antigen 1 (α1β1 integrin). (b) Long after the pathogen has been eliminated from the barrier tissue and inflammation has resolved, populations of TRM cells remain behind in the tissue. These TRM cells retain the tissue-homing molecules originally imprinted on them and acquire a molecular program that contributes to the maintenance of these cells in peripheral tissue. In parallel, circulating memory T cells are generated, and these have the capacity to enter lymph node and recirculate into blood and tissue. Recent evidence suggests that the same naive T cell may give rise to both TRM cells and TCM cells or circulating T cells38. Adapted with permission from ref. 113, Nature Publishing Group.

  2. The role of TRM cells in tissue-specific autoimmune and inflammatory disease.
    Figure 2: The role of TRM cells in tissue-specific autoimmune and inflammatory disease.

    Right, diseases of lung, gut and skin clearly or potentially mediated by pathologically activated TRM cells. Left, diseases of normally sterile non-barrier tissues mediated by infiltrating T cells that have acquired the properties of TRM cells. Disease states in normal font indicate that there is experimental evidence supporting TRM cell causation, whereas disease states in italic font are speculation on the part of the authors. GVHD, graft-versus-host disease.


  1. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708712 (1999).
  2. Fuhlbrigge, R.C., Kieffer, J.D., Armerding, D. & Kupper, T.S. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389, 978981 (1997).
  3. Mackay, C.R. et al. Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells. Eur. J. Immunol. 22, 887895 (1992).
  4. Jiang, X. et al. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483, 227231 (2012).
  5. Clark, R.A. Resident memory T cells in human health and disease. Sci. Transl. Med. 7, 269rv261 (2015).
  6. Mackay, L.K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 12941301 (2013).
  7. Wakim, L.M. et al. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J. Immunol. 189, 34623471 (2012).
  8. von Andrian, U.H. & Mempel, T.R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867878 (2003).
  9. Tubo, N.J. et al. Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153, 785796 (2013).
  10. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 10201034 (2000).
  11. Liu, L., Fuhlbrigge, R.C., Karibian, K., Tian, T. & Kupper, T.S. Dynamic programming of CD8+ T cell trafficking after live viral immunization. Immunity 25, 511520 (2006).
  12. Sallusto, F. & Lanzavecchia, A. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur. J. Immunol. 39, 20762082 (2009).
  13. Campbell, D.J. & Butcher, E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135141 (2002).
  14. Picker, L.J. et al. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J. Immunol. 150, 11221136 (1993).
  15. Borowitz, M.J., Weidner, A., Olsen, E.A. & Picker, L.J. Abnormalities of circulating T-cell subpopulations in patients with cutaneous T-cell lymphoma: cutaneous lymphocyte-associated antigen expression on T cells correlates with extent of disease. Leukemia 7, 859863 (1993).
  16. Berg, E.L. et al. The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1. J. Exp. Med. 174, 14611466 (1991).
  17. Campbell, J.J. et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776780 (1999).
  18. Campbell, J.J., Pan, J. & Butcher, E.C. Cutting edge: developmental switches in chemokine responses during T cell maturation. J. Immunol. 163, 23532357 (1999).
  19. Homey, B. et al. CCL27-CCR10 interactions regulate T cell–mediated skin inflammation. Nat. Med. 8, 157165 (2002).
  20. Siewert, C. et al. Induction of organ-selective CD4+ regulatory T cell homing. Eur. J. Immunol. 37, 978989 (2007).
  21. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527538 (2004).
  22. Briskin, M. et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97110 (1997).
  23. Zabel, B.A. et al. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190, 12411256 (1999).
  24. Chong, B.F., Murphy, J.E., Kupper, T.S. & Fuhlbrigge, R.C. E-selectin, thymus- and activation-regulated chemokine/CCL17, and intercellular adhesion molecule-1 are constitutively coexpressed in dermal microvessels: a foundation for a cutaneous immunosurveillance system. J. Immunol. 172, 15751581 (2004).
  25. Kupper, T.S. & Fuhlbrigge, R.C. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. 4, 211222 (2004).
  26. Mackay, C.R. & von Andrian, U.H. Immunology. Memory T cells—local heroes in the struggle for immunity. Science 291, 23232324 (2001).
  27. Robert, C. & Kupper, T.S. Inflammatory skin diseases, T cells, and immune surveillance. N. Engl. J. Med. 341, 18171828 (1999).
  28. Hogan, R.J. et al. Activated antigen-specific CD8+ T cells persist in the lungs following recovery from respiratory virus infections. J. Immunol. 166, 18131822 (2001).
  29. Wei, C.H. et al. Tissue-resident memory CD8+ T cells can be deleted by soluble, but not cross-presented antigen. J. Immunol. 175, 66156623 (2005).
  30. Wu, T. et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 95, 215224 (2014).
  31. Kuklin, N.A. et al. α4β7 independent pathway for CD8+ T cell-mediated intestinal immunity to rotavirus. J. Clin. Invest. 106, 15411552 (2000).
  32. Schlapbach, C. et al. Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci. Transl. Med. 6, 219ra218 (2014).
  33. Seneschal, J., Clark, R.A., Gehad, A., Baecher-Allan, C.M. & Kupper, T.S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873884 (2012).
  34. Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510513 (2009).
  35. Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463467 (2012).
  36. 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, 70377042 (2012).
  37. Iijima, N. & Iwasaki, A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 9398 (2014).
  38. Gaide, O. et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat. Med. 21, 647653 (2015).
  39. 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. 193, 20672071 (2014).
  40. Laidlaw, B.J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633645 (2014).
  41. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 24132417 (2001).
  42. Klonowski, K.D. et al. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20, 551562 (2004).
  43. Mueller, S.N., Gebhardt, T., Carbone, F.R. & Heath, W.R. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137161 (2013).
  44. Bevan, M.J. Memory T cells as an occupying force. Eur. J. Immunol. 41, 11921195 (2011).
  45. Gebhardt, T., Mueller, S.N., Heath, W.R. & Carbone, F.R. Peripheral tissue surveillance and residency by memory T cells. Trends Immunol. 34, 2732 (2013).
  46. Carbone, F.R., Mackay, L.K., Heath, W.R. & Gebhardt, T. Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. Curr. Opin. Immunol. 25, 329333 (2013).
  47. Mueller, S.N., Zaid, A. & Carbone, F.R. Tissue-resident T cells: dynamic players in skin immunity. Front. Immunol. 5, 332 (2014).
  48. Sheridan, B.S. et al. Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity 40, 747757 (2014).
  49. Beura, L.K. & Masopust, D. SnapShot: resident memory T cells. Cell 157, 14881488 (2014).
  50. Turner, D.L. & Farber, D.L. Mucosal resident memory CD4 T cells in protection and immunopathology. Front. Immunol. 5, 331 (2014).
  51. Shiow, L.R. et al. CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540544 (2006).
  52. Mackay, L.K. et al. Cutting Edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J. Immunol. 194, 20592063 (2015).
  53. Skon, C.N. et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 12851293 (2013).
  54. Cyster, J.G. & Schwab, S.R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 6994 (2012).
  55. Bromley, S.K., Thomas, S.Y. & Luster, A.D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat. Immunol. 6, 895901 (2005).
  56. 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, 970976 (2013).
  57. 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, 279ra239 (2015).
  58. Hadley, G.A. & Higgins, J.M. Integrin αEβ7: molecular features and functional significance in the immune system. Adv. Exp. Med. Biol. 819, 97110 (2014).
  59. Piet, B. et al. CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. J. Clin. Invest. 121, 22542263 (2011).
  60. Nestle, F.O., Di Meglio, P., Qin, J.Z. & Nickoloff, B.J. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679691 (2009).
  61. Shimamura, K. & Takeichi, M. Local and transient expression of E-cadherin involved in mouse embryonic brain morphogenesis. Development 116, 10111019 (1992).
  62. 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 410, 101105 (2001).
  63. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524530 (2009).
  64. Bergsbaken, T. & Bevan, M.J. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. Nat. Immunol. 16, 406414 (2015).
  65. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4 and CD8 T cells. Nature 477, 216219 (2011).
  66. 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, 117ra117 (2012).
  67. Casey, K.A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 48664875 (2012).
  68. Kadow, S. et al. Aryl hydrocarbon receptor is critical for homeostasis of invariant γδ T cells in the murine epidermis. J. Immunol. 187, 31043110 (2011).
  69. Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl. Acad. Sci. USA 111, 53075312 (2014).
  70. Schenkel, J.M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98101 (2014).
  71. Ariotti, S. et al. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101105 (2014).
  72. Clark, R.A. Skin-resident T cells: the ups and downs of on site immunity. J. Invest. Dermatol. 130, 362370 (2010).
  73. Clark, R.A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 44314439 (2006).
  74. Clark, R.A. et al. A novel method for the isolation of skin resident T cells from normal and diseased human skin. J. Invest. Dermatol. 126, 10591070 (2006).
  75. Clark, R.A. & Kupper, T.S. IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 109, 194202 (2007).
  76. Hijnen, D. et al. CD8+ T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-γ, IL-13, IL-17, and IL-22. J. Invest. Dermatol. 133, 973979 (2013).
  77. Liu, L. et al. Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nat. Med. 16, 224227 (2010).
  78. Zhu, J. et al. Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection. Nature 497, 494497 (2013).
  79. Tomura, M. et al. Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice. J. Clin. Invest. 120, 883893 (2010).
  80. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553564 (2010).
  81. Ruane, D.T. & Lavelle, E.C. The role of CD103+ dendritic cells in the intestinal mucosal immune system. Front. Immunol. 2, 25 (2011).
  82. Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187197 (2013).
  83. Tse, S.W., Cockburn, I.A., Zhang, H., Scott, A.L. & Zavala, F. Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites. Genes Immun. 14, 302309 (2013).
  84. Yanagisawa, K. et al. Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C. J. Viral Hepat. 20, 556565 (2013).
  85. Turner, D.L. et al. Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol. 7, 501510 (2014).
  86. Hu, Y., Lee, Y.T., Kaech, S.M., Garvy, B. & Cauley, L.S. Smad4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells. J. Immunol. 194, 24072414 (2015).
  87. Purwar, R. et al. Resident memory T cells (T(RM)) are abundant in human lung: diversity, function, and antigen specificity. PLoS One 6, e16245 (2011).
  88. Kupper, T.S. Old and new: recent innovations in vaccine biology and skin T cells. J. Invest. Dermatol. 132, 829834 (2012).
  89. Iijima, N. & Iwasaki, A. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 9398 (2014).
  90. Cuburu, N. et al. Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. J. Clin. Invest. 122, 46064620 (2012).
  91. Cuburu, N. et al. Topical herpes simplex virus 2 (HSV-2) vaccination with human papillomavirus vectors expressing gB/gD ectodomains induces genital-tissue-resident memory CD8+ T cells and reduces genital disease and viral shedding after HSV-2 challenge. J. Virol. 89, 8396 (2015).
  92. Maldonado, L. et al. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci. Transl. Med. 6, 221ra213 (2014).
  93. Shiohara, T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr. Opin. Allergy Clin. Immunol. 9, 316321 (2009).
  94. Suarez-Farinas, M., Fuentes-Duculan, J., Lowes, M.A. & Krueger, J.G. Resolved psoriasis lesions retain expression of a subset of disease-related genes. J. Invest. Dermatol. 131, 391400 (2011).
  95. Clark, R.A. Gone but not forgotten: lesional memory in psoriatic skin. J. Invest. Dermatol. 131, 283285 (2011).
  96. Cheuk, S. et al. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J. Immunol. 192, 31113120 (2014).
  97. Honda, T., Egawa, G., Grabbe, S. & Kabashima, K. Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J. Invest. Dermatol. 133, 303315 (2013).
  98. Campbell, J.J., Clark, R.A., Watanabe, R. & Kupper, T.S. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 116, 767771 (2010).
  99. Kleinschek, M.A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525534 (2009).
  100. Sasaki, K. et al. Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells. J. Immunol. 192, 30293042 (2014).
  101. Debnath, M. & Berk, M. Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr. Bull. 40, 14121421 (2014).
  102. Sherlock, J.P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4CD8 entheseal resident T cells. Nat. Med. 18, 10691076 (2012).
  103. Henderson, L.A. et al. A161: novel 3-dimensional explant method facilitates the study of lymphocyte populations in the synovium and reveals a large population of resident memory T cells in rheumatoid arthritis. Arthritis Rheum. 66 (suppl. 11), S209 (2014).
  104. Zhou, G. et al. Identification of systemically expanded activated T cell clones in MRL/lpr and NZB/W F1 lupus model mice. Clin. Exp. Immunol. 136, 448455 (2004).
  105. Feng, Y. et al. CD103 expression is required for destruction of pancreatic islet allografts by CD8+ T cells. J. Exp. Med. 196, 877886 (2002).
  106. Wang, D. et al. Regulation of CD103 expression by CD8+ T cells responding to renal allografts. J. Immunol. 172, 214221 (2004).
  107. Ding, R. et al. CD103 mRNA levels in urinary cells predict acute rejection of renal allografts. Transplantation 75, 13071312 (2003).
  108. Boldison, J. et al. Tissue-resident exhausted effector memory CD8+ T cells accumulate in the retina during chronic experimental autoimmune uveoretinitis. J. Immunol. 192, 45414550 (2014).
  109. Freeman, G.J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 10271034 (2000).
  110. Webb, J.R., Milne, K., Watson, P., Deleeuw, R.J. & Nelson, B.H. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin. Cancer Res. 20, 434444 (2014).
  111. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134144 (2013).
  112. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320330 (2015).
  113. Sheridan, B.S. & Lefrançois, L. Regional and mucosal memory T cells. Nat. Immunol. 12, 485491 (2011).
  114. Jiang, X., Campbell, J.J. & Kupper, T.S. Embryonic trafficking of γδ T cells to skin is dependent on E/P selectin ligands and CCR4. Proc. Natl. Acad. Sci. USA 107, 74437448 (2010).
  115. Gray, E.E., Suzuki, K. & Cyster, J.G. Cutting edge: identification of a motile IL-17-producing γδ T cell population in the dermis. J. Immunol. 186, 60916095 (2011).
  116. Sumaria, N. et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J. Exp. Med. 208, 505518 (2011).
  117. Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596610 (2011).
  118. Sanchez Rodriguez, R. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 10271036 (2014).
  119. Hansen, S.G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523527 (2011).
  120. Gardner, J.M., Evans, K.G., Musiek, A., Rook, A.H. & Kim, E.J. Update on treatment of cutaneous T-cell lymphoma. Curr. Opin. Oncol. 21, 131137 (2009).
  121. Watanabe, R., Teague, J.E., Fisher, D.C., Kupper, T.S. & Clark, R.A. Alemtuzumab therapy for leukemic cutaneous T-cell lymphoma: diffuse erythema as a positive predictor of complete remission. JAMA Dermatol. 150, 776779 (2014).
  122. Rao, U.N., Lee, S.J., Luo, W., Mihm, M.C. Jr. & Kirkwood, J.M. Presence of tumor-infiltrating lymphocytes and a dominant nodule within primary melanoma are prognostic factors for relapse-free survival of patients with thick (t4) primary melanoma: pathologic analysis of the e1690 and e1694 intergroup trials. Am. J. Clin. Pathol. 133, 646653 (2010).
  123. Tumeh, P.C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568571 (2014).
  124. Webb, J.R., Milne, K. & Nelson, B.H. Location, location, location: CD103 demarcates intraepithelial, prognostically favorable CD8 tumor-infiltrating lymphocytes in ovarian cancer. Oncoimmunology 3, e27668 (2014).
  125. 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, 34753486 (2015).

Download references

Author information


  1. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Chang Ook Park &
    • Thomas S Kupper

Competing financial interests

T.S.K. is an inventor on US Patent 8691502, assigned to TremRx, Inc.

Corresponding author

Correspondence to:

Author details

Additional data