Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Local heroes or villains: tissue-resident memory T cells in human health and disease

Abstract

Tissue-resident memory T (TRM) cells are increasingly associated with the outcomes of health and disease. TRM cells can mediate local immune protection against infections and cancer, which has led to interest in TRM cells as targets for vaccination and immunotherapies. However, these cells have also been implicated in mediating detrimental pro-inflammatory responses in autoimmune skin diseases such as psoriasis, alopecia areata, and vitiligo. Here, we summarize the biology of TRM cells established in animal models and in translational human studies. We review the beneficial effects of TRM cells in mediating protective responses against infection and cancer and the adverse role of TRM cells in driving pathology in autoimmunity. A further understanding of the breadth and mechanisms of TRM cell activity is essential for the safe design of strategies that manipulate TRM cells, such that protective responses can be enhanced without unwanted tissue damage, and pathogenic TRM cells can be eliminated without losing local immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of TRM cell function in human disease.

Similar content being viewed by others

References

  1. Mackay, L. & Kallies, A. Transcriptional regulation of tissue-resident lymphocytes. Trends Immunol. 38, 94–103 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Mueller, S. & Mackay, L. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Masopust, D., Vezys, V., Marzo, A. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Schenkel, J. M. et al. IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells. J. Immunol. 196, 3920–3926 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187–197 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Savas, P. et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med 24, 986–993 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Klonowski, K. D. et al. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20, 551–562 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Steinert, E. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Anderson, K. et al. Cutting edge: intravascular staining redefines lung CD8 T cell responses. J. Immunol. 189, 2702–2706 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Vesely, M. et al. Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection. Cell 178, 1176–1188.e15 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  18. Iijima, N. & Iwasaki, A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hondowicz, B. D. et al. Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma. Immunity 44, 155–166 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Beura, L. K. et al. CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses. J. Exp. Med. 216, jem.20181365 (2019).

    Article  CAS  Google Scholar 

  22. Teijaro, J. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Kumar, B. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oja, A. et al. Trigger-happy resident memory CD4(+) T cells inhabit the human lungs. Mucosal Immunol. 11, 654–667 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Kleinschek, M. A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wakim, L. et al. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J. Immunol. 189, 3462–3471 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Skon, C. et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 1285–1293 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Mackay, L. et al. Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J. Immunol. 194, 2059–2063 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Ma, C., Mishra, S., Demel, E. L., Liu, Y. & Zhang, N. TGF-β controls the formation of kidney-resident T cells via promoting effector T cell extravasation. J. Immunol. 198, 749–756 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Fernandez-Ruiz, D. et al. Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. Immunity 45, https://doi.org/10.1016/j.immuni.2016.08.011 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Bergsbaken, T. & Bevan, M. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8(+) T cells responding to infection. Nat. Immunol. 16, 406–414 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sheridan, B. et al. Oral infection drives a distinct population of intestinal resident memory CD8(+) T cells with enhanced protective function. Immunity 40, 747–757 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pallett, L. et al. IL-2(high) tissue-resident T cells in the human liver: sentinels for hepatotropic infection. J. Exp. Med. 214, 1567 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kumar, B. V. et al. Functional heterogeneity of human tissue-resident memory T cells based on dye efflux capacities. JCI Insight 3, e123568 (2018).

    Article  PubMed Central  Google Scholar 

  37. Hombrink, P. et al. Programs for the persistence, vigilance and control of human CD8(+) lung-resident memory T cells. Nat. Immunol. 17, 1467–1478 (2016).

    Article  CAS  PubMed  Google Scholar 

  38. Pizzolla, A. & Wakim, L. M. Memory T cell dynamics in the lung during influenza virus infection. J. Immunol. 202, 374–381 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Smith, C. J., Caldeira-Dantas, S., Turula, H. & Snyder, C. M. Murine CMV infection induces the continuous production of mucosal resident T cells. Cell Rep. 13, 1137–1148 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thom, J., Weber, T., Walton, S., Torti, N. & Oxenius, A. The salivary gland acts as a sink for tissue-resident memory CD8+ T cells, facilitating protection from local cytomegalovirus infection. Cell Rep. 13, 1125 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, N. & Bevan, M. J. Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39, 687–696 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Milner, J. et al. Runx3 programs CD8(+) T cell residency in non-lymphoid tissues and tumours. Nature 552, 253–257 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, C. et al. The Transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality. Immunity 51, 491–507.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 1–26 (2019).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Beura, L. K. et al. Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Mackay, L. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pizzolla, A. et al. Resident memory CD8+ T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci. Immunol. 2, eaam6970 (2017).

    Article  PubMed  Google Scholar 

  52. 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, 215–224 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. 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, 224 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ganesan, A. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 18, 940–950 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Edwards, J. et al. CD103(+) tumor-resident CD8(+) T cells are associated with improved survival in immunotherapy-naive melanoma patients and expand significantly during anti-PD-1 treatment. Clin. Cancer Res. 24, 3036–3045 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Wang, B. et al. CD103+ tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder. J. Urology 194, 556–562 (2015).

    Article  CAS  Google Scholar 

  57. Bösmüller, H.-C. et al. Combined immunoscore of CD103 and CD3 identifies long-term survivors in high-grade serous ovarian cancer. Int. J. Gynecol. Cancer 26, 671–679 (2016).

    Article  PubMed  Google Scholar 

  58. Workel, H. H. et al. CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma. Eur. J. Cancer 60, 1–11 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Lian, C. et al. Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury. Mod. Pathol. 27, 788–799 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Snyder, M. E. et al. Generation and persistence of human tissue-resident memory T cells in lung transplantation. Sci. Immunol. 4, eaav5581 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zuber, J. et al. Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome. Sci. Immunol. 1, eaah3732 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bartolomé-Casado, R. et al. Resident memory CD8 T cells persist for years in human small intestine. J. Exp. Med. https://doi.org/10.1084/jem.20190414 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Thome, J. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Clark, R. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. 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, 279ra39–279ra39 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Casey, K. A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866–4875 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Hofmann, M. & Pircher, H. E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands. Proc. Natl Acad. Sci. USA 108, 16741–16746 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Topham, D. & Reilly, E. Tissue-resident memory CD8(+) T cells: from phenotype to function. Front. Immunol. 9, 515 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Liu, Y., Ma, C. & Zhang, N. Tissue-specific control of tissue-resident memory T cells. Crit. Rev. Immunol. 38, 79–103 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wherry, E. & Ahmed, R. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78, 5535–5545 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Remakus, S. & Sigal, L. J. Advances in experimental medicine and biology. Adv. Exp. Med. Biol. 785, 77–86 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Klenerman, P. The (gradual) rise of memory inflation. Immunol. Rev. 283, 99–112 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Philip, M. & Schietinger, A. Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections. Curr. Opin. Immunol. 58, 98–103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Muruganandah, V., Sathkumara, H. D., Navarro, S. & Kupz, A. A systematic review: the role of resident memory T cells in infectious diseases and their relevance for vaccine development. Front. Immunol. 9, 1574 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. de Bree, G. et al. Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung. J. Infect. Dis. 195, 1718 (2007).

    Article  PubMed  Google Scholar 

  76. Piet, B. et al. CD8(+) T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. J. Clin. Investig. 121, 2254 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Turner, D. et al. Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol. 7, 501 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Koutsakos, M. et al. Human CD8+ T cell cross-reactivity across influenza A, B and C viruses. Nat. Immunol. 20, 613–625 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. de Bree, G. J. et al. Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung. J. Exp. Med. 202, 1433–1442 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Pizzolla, A. et al. Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles. J. Clin. Investig. 128, 721 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Sridhar, S. et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat. Med. 19, nm.3350 (2013).

    Article  CAS  Google Scholar 

  82. Zens, K., Chen, J. & Farber, D. Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection. J. Clin. Invest. Insight 1, e85832 (2016).

    Google Scholar 

  83. Slutter, B. et al. Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci. Immunol. 2, eaag2031 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Sant, S. et al. Single-cell approach to influenza-specific CD8(+) T cell receptor repertoires across different age groups, tissues, and following influenza virus infection. Front. Immunol. 9, 1453 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Clemens, E., van de Sandt, C., Wong, S., Wakim, L. & Valkenburg, S. Harnessing the power of T cells: the promising hope for a universal influenza vaccine. Vaccines (Basel) 6, E18 (2018).

  86. He, X.-S. et al. Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines. J. Virol. 80, 11756–11766 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cheng, X. et al. Evaluation of the humoral and cellular immune responses elicited by the live attenuated and inactivated influenza vaccines and their roles in heterologous protection in ferrets. J. Infect. Dis. 208, 594 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Jang, Y. et al. Cold-adapted X-31 live attenuated 2009 pandemic H1N1 influenza vaccine elicits protective immune responses in mice and ferrets. Vaccine 31, 1320 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Sommer, C., Resch, B. & Simoes, E. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol. J. 5, 144 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Falsey, A., Hennessey, P., Formica, M., Cox, C. & Walsh, E. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Habibi, JozwikA. et al. Impaired antibody-mediated protection and defective IgA B-cell memory in experimental infection of adults with respiratory syncytial virus. Am. J. Respir. Crit. Care Med. 191, 1040 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Heidema, J. et al. CD8+ T cell responses in bronchoalveolar lavage fluid and peripheral blood mononuclear cells of infants with severe primary respiratory syncytial virus infections. J. Immunol. (Baltim., Md: 1950) 179, 8410 (2007).

    CAS  Google Scholar 

  93. Jozwik, A. et al. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat. Commun. 6, 10224 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Cannon, M., Openshaw, P. & Askonas Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J. Exp. Med. 168, 1163 (1988).

    Article  CAS  PubMed  Google Scholar 

  95. Alwan, W., Record, F. & Openshaw, P. CD4+ T cells clear virus but augment disease in mice infected with respiratory syncytial virus. Comparison with the effects of CD8+ T cells. Clin. Exp. Immunol. 88, 527 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Walsh, E. E., Peterson, D. R., Kalkanoglu, A. E., Lee, F. & Falsey, A. R. Viral shedding and immune responses to respiratory syncytial virus infection in older adults. J. Infect. Dis. 207, 1424–1432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li, H. et al. Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys. PLoS ONE 12, e0187642 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Kinnear, E. et al. Airway T cells protect against RSV infection in the absence of antibody. Mucosal. Immunol. 11, 290 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Morabito, K. et al. Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung. Mucosal Immunol. 10, 545–554 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Zhang, L. et al. CpG in combination with an inhibitor of notch signaling suppresses formalin-inactivated respiratory syncytial virus-enhanced airway hyperresponsiveness and inflammation by inhibiting Th17 memory responses and promoting tissue-resident memory cells in lungs. J. Virol. 91, e021111-16 (2017).

  101. Whitley, R. J. & Roizman, B. Herpes simplex virus infections. Lancet 357, 1513–1518 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Mark, K. E. et al. Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J. Infect. Dis. 198, 1141–1149 (2008).

    Article  PubMed  Google Scholar 

  103. Koelle, D. M., Abbo, H., Peck, A., Ziegweid, K. & Corey, L. Direct recovery of herpes simplex virus (HSV)-specific T lymphocyte clones from recurrent genital HSV-2 lesions. J. Infect. Dis. 169, 956–961 (1994).

    Article  CAS  PubMed  Google Scholar 

  104. Knickelbein, J. E. et al. Noncytotoxic lytic granule–mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268–271 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wakim, L. M., Gebhardt, T., Heath, W. R. & Carbone, F. R. Cutting edge: local recall responses by memory T cells newly recruited to peripheral nonlymphoid tissues. J. Immunol. 181, 5837–5841 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Posavad, C. et al. Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract. Mucosal Immunol. 10, 1259 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schiffer, J. T. et al. A fixed spatial structure of CD8+ T cells in tissue during chronic HSV-2 infection. J. Immunol. (Balt. Md., 1950) 201, 1522–1535 (2018).

    Article  CAS  Google Scholar 

  109. Kotton, C. CMV: prevention, diagnosis and therapy. Am. J. Transpl. 13, 24–40 (2013).

    Article  Google Scholar 

  110. Karrer, U. et al. Memory inflation: continuous accumulation of antiviral CD8 + T cells over time. J. Immunol. 170, 2022–2029 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Baumann, N. S. et al. Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool. PLos Pathog. 15, e1007785 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gordon, C. et al. Induction and maintenance of CX3CR1-intermediate peripheral memory CD8 + T cells by persistent viruses and vaccines. Cell Rep. 23, 768–782 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Smith, C., Caldeira-Dantas, S., Turula, H. & Snyder, C. Murine CMV infection induces the continuous production of mucosal resident T cells. Cell Rep. 13, 1137 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Baumann, N. S. et al. Tissue maintenance of CMV-specific inflationary memory T cells by IL-15. PLos Pathog. 14, e1006993 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Highton, A. J. et al. Single-cell transcriptome analysis of CD8+ T-cell memory inflation. Wellcome Open Res. 4, 78 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Morabito, K. M. et al. Memory inflation drives tissue-resident memory CD8+ T cell maintenance in the lung after intranasal vaccination with murine cytomegalovirus. Front. Immunol. 9, 1861 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Gordon, C. L. et al. Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection. J. Exp. Med. 214, jem.20160758 (2017).

    Article  CAS  Google Scholar 

  119. Ward, S. M. et al. Virus-specific CD8+ T lymphocytes within the normal human liver. Eur. J. Immunol. 34, 1526–1531 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Remmerswaal, E. B. et al. Human virus-specific effector-type T cells accumulate in blood but not in lymph nodes. Blood 119, 1702–1712 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Letsch, A. et al. CMV-specific central memory T cells reside in bone marrow. Eur. J. Immunol. 37, 3063–3068 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Palendira, U. et al. Selective accumulation of virus-specific CD8+ T cells with unique homing phenotype within the human bone marrow. Blood 112, 3293–3302 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Akulian, J., Pipeling, M., John, E., Orens, J. & Lechtzin, N. High-quality CMV-specific CD4+ memory is enriched in the lung allograft and is associated with mucosal viral control. Am. J. Transpl. 13, 146–156 (2013).

    Article  CAS  Google Scholar 

  124. Remmerswaal, E. B. et al. Clonal evolution of CD8+ T cell responses against latent viruses: relationship among phenotype, localization, and function. J. Virol. 89, 568–580 (2015).

    Article  PubMed  CAS  Google Scholar 

  125. Sitki-Green, D., Covington, M. & Raab-Traub, N. Compartmentalization and transmission of multiple Epstein–Barr virus strains in asymptomatic carriers. J. Virol. 77, 1840–1847 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Woon, H. et al. Compartmentalization of total and virus-specific tissue-resident memory CD8+ T cells in human lymphoid organs. PLoS Pathog. 12, e1005799 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Woodberry, T. et al. αEβ7 (CD103) expression identifies a highly active, tonsil-resident effector-memory CTL population. J. Immunol. 175, 4355–4362 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Hislop, A. D. et al. Tonsillar homing of Epstein–Barr virus–specific CD8+ T cells and the virus–host balance. J. Clin. Invest. 115, 2546–2555 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Shannon-Lowe, C. & Rickinson, A. The global landscape of EBV-associated tumors. Front. Oncol. 9, 713 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Stelma, F. et al. Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity. Sci. Rep. (UK) 7, 6172 (2017).

    Article  CAS  Google Scholar 

  131. Gibbs, A. et al. HIV-infected women have high numbers of CD103-CD8+ T cells residing close to the basal membrane of the ectocervical epithelium. J. Infect. Dis. https://doi.org/10.1093/infdis/jix661 (2017).

    Article  CAS  Google Scholar 

  132. Buggert, M. et al. Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue. Sci. Immunol. 3, eaar4526 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Kiniry, B. E. et al. Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection. Mucosal Immunol. 11, 909 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Moylan, D. C. et al. Diminished CD103 (aEb7) expression on resident T cells from the female genital tract of HIV-positive women. Pathog. Immun. 1, 371–389 (2016).

    Article  PubMed  Google Scholar 

  135. Damouche, A. et al. High proportion of PD-1-expressing CD4+ T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence. Eur. J. Immunol. 47, 2113–2123 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. Tan, H.-X. et al. Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime–boost immunization. Mucosal Immunol. 11, 994 (2017).

    Article  PubMed  CAS  Google Scholar 

  137. Zaric, M. et al. Long-lived tissue resident HIV-1 specific memory CD8+ T cells are generated by skin immunization with live virus vectored microneedle arrays. J. Control Rel. 268, 166–175 (2017).

    Article  CAS  Google Scholar 

  138. Adnan, S. et al. Persistent low-level replication of SIVΔnef drives maturation of antibody and CD8 T cell responses to induce protective immunity against vaginal SIV infection. PLoS Pathog. 12, e1006104 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Farhood, B., Najafi, M. & Mortezaee, K. CD8 + cytotoxic T lymphocytes in cancer immunotherapy: a review. J. Cell Physiol. 234, 8509–8521 (2018).

    Article  PubMed  CAS  Google Scholar 

  141. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dhodapkar, K. Role of tissue-resident memory in intra-tumor heterogeneity and response to immune checkpoint blockade. Front Immunol. 9, 1655 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Boddupalli, C. et al. Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells. JCI Insight 1, e88955 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Salerno, E. P., Olson, W. C., Imming, C., Shea, S. & Slingluff, C. L. T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins. Int. J. Cancer 134, 563–574 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 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).

    Article  CAS  PubMed  Google Scholar 

  146. Wang, Z.-Q. et al. CD103 and intratumoral immune response in breast cancer. Clin. Cancer Res. 22, clincanres.0732.2016 (2016).

    Google Scholar 

  147. Quinn, E., Hawkins, N., Yip, Y., Suter, C. & Ward, R. CD103+ intraepithelial lymphocytes—a unique population in microsatellite unstable sporadic colorectal cancer. Eur. J. Cancer 39, 469–475 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. de Vries, N. L. et al. High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity. Gut gutjnl-2019-318672 (2019).

  149. Hartana, C. et al. Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer. Clin. Exp. Immunol. 194, 39–53 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Webb, J. R. et al. Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (αE/β7 Integrin) in high-grade serous ovarian cancer. Gynecol. Oncol. 118, 228–236 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Webb, J., Milne, K. & Nelson, B. Location, location, location: CD103 demarcates intraepithelial, prognostically favorable CD8(+) tumor-infiltrating lymphocytes in ovarian cancer. Oncoimmunology 3, e27668 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Komdeur, F. L. et al. CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer. Oncoimmunology 6, e1338230 (2017).

    Article  CAS  Google Scholar 

  153. Floc’h, A. et al. αEβ7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J. Exp. Med. 204, 559–570 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Molodtsov, A. & Turk, M. Tissue resident CD8 memory T cell responses in cancer and autoimmunity. Front. Immunol. 9, 2810 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Clarke, J. et al. Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer. J. Exp. Med. https://doi.org/10.1084/jem.20190249 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  158. Franciszkiewicz, K. et al. CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions. Cancer Res. 73, 617–628 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Amsen, D., van Gisbergen, K., Hombrink, P. & van Lier, R. Tissue-resident memory T cells at the center of immunity to solid tumors. Nat. Immunol. 19, 538–546 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  162. Molina, J. R., Yang, P., Cassivi, S. D., Schild, S. E. & Adjei, A. A. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 83, 584–594 (2008).

    Article  PubMed  Google Scholar 

  163. Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary Bacillus Calmette-guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–182 (1976).

    Article  CAS  PubMed  Google Scholar 

  164. Alifrangis, C., McGovern, U., Freeman, A., Powles, T. & Linch, M. Molecular and histopathology directed therapy for advanced bladder cancer. Nat. Rev. Urol. 16, 465–483 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Jou, A. & Hess, J. Epidemiology and molecular biology of head and neck cancer. Oncol. Res. Treat. 40, 328–332 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Badoual, C. et al. Prognostic value of tumor-infiltrating CD4+ T-Cell subpopulations in head and neck cancers. Clin. Cancer Res. 12, 465–472 (2006).

    Article  CAS  PubMed  Google Scholar 

  167. Badoual, C. et al. PD-1–expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 73, 128–138 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Welters, M. et al. Intratumoral HPV16-specific T cells constitute a type I-oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer. Clin. Cancer Res. 24, 634–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  169. Fergusson, J. et al. CD161intCD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut. Mucosal Immunol. 9, 401 (2016).

    Article  CAS  PubMed  Google Scholar 

  170. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, nm.3909 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rodriguez, R. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 1027–1036 (2014).

    Article  CAS  Google Scholar 

  173. Park, C. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Machado-Santos, J. et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 141, 2066–2082 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Kuric, E. et al. Demonstration of tissue resident memory CD8 T cells in insulitic lesions in adult patients with recent-onset type 1 diabetes. Am. J. Pathol. 187, 581–588 (2017).

    Article  CAS  PubMed  Google Scholar 

  176. Zundler, S. et al. Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation. Nat. Immunol. 20, 288–300 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Ho, A. W. & Kupper, T. S. T cells and the skin: from protective immunity to inflammatory skin disorders. Nat. Rev. Immunol. 19, 490–502 (2019).

    Article  CAS  PubMed  Google Scholar 

  179. Hawkes, J., Chan, T. & Krueger, J. Psoriasis pathogenesis and the development of novel targeted immune therapies. J. Allergy Clin. Immunol. 140, 645 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Teunissen, M. et al. The IL-17A-producing CD8+ T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells. J. Invest. Dermatol. 134, 2898 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. Bhushan, M. et al. Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial. Br. J. Dermatol. 146, 824 (2002).

    Article  CAS  PubMed  Google Scholar 

  182. Boyman, O., Hefti, H., Conrad, C., Nickoloff, B. & ter, Nestle, F. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J. Exp. Med. 199, 731 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Gilhar, A., Etzioni, A. & Paus, R. Alopecia areata. N. Engl. J. Med. 366, 1515 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Pratt HC, L. E. Jr., Messenger, A. G., Christiano, A. M. & Sundberg, J. P. Alopecia areata. Nat. Rev. Dis. Prim. 3, nrdp201711 (2017).

    Google Scholar 

  187. Xing, L. et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med. 20, 1043 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Gilhar, A., Ullmann, Y., Berkutzki, T. & Kalish, R. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J. Clin. Invest. 101, 62–67 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Li, J. et al. Laser capture microdissection reveals transcriptional abnormalities in alopecia areata before, during, and after active hair loss. J. Invest. Dermatol. 136, 715 (2016).

    Article  CAS  PubMed  Google Scholar 

  190. Ibrahim, O., Bayart, C., Hogan, S., Piliang, M. & Bergfeld, W. Treatment of alopecia areata with tofacitinib. JAMA Dermatol. 153, 600 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  191. de Jong, A. et al. High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata. JCI Insight 3, e121949 (2018).

  192. Bishnoi, A. & Parsad, D. Clinical and molecular aspects of vitiligo treatments. Int. J. Mol. Sci. 19, 1509 (2018).

    Article  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Prosser, A. C., Kallies, A. & Lucas, M. Tissue-resident lymphocytes in solid organ transplantation. Transplantation 102, 378–386 (2018).

    Article  PubMed  Google Scholar 

  195. Turner, D. L., Gordon, C. L. & Farber, D. L. Tissue-resident T cells, in situ immunity and transplantation. Immunol. Rev. 258, 150–166 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

S.C.S. is supported by an Oxford-Celgene Postdoctoral Fellowship. C.L.G. is supported by an NHMRC Early Career Fellowship (GNT 1160963). P.K. is supported by an Oxford and NIHR Senior Fellowship (WT10966MA). L.K.M. is a Senior Medical Research Fellow supported by the Sylvia and Charles Viertel Charitable Foundation.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to P. Klenerman or L. K. Mackay.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sasson, S.C., Gordon, C.L., Christo, S.N. et al. Local heroes or villains: tissue-resident memory T cells in human health and disease. Cell Mol Immunol 17, 113–122 (2020). https://doi.org/10.1038/s41423-019-0359-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0359-1

Keywords

This article is cited by

Search

Quick links