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Tissue-resident memory T cell

Tissue-resident memory T cells or TRM cells represent a subset of a long-lived memory T cells that occupies epithelial, mucosal and other tissues (skin, mucosa, lung, brain, pancreas, gastrointestinal tract) without recirculating. TRM cells are transcriptionally, phenotypically and functionally distinct from central memory (TCM) and effector memory (TEM) T cells which recirculate between blood, the T cell zones of secondary lymphoid organ, lymph and nonlymphoid tissues. Moreover, TRM cells themself represent a diverse populations because of the specializations for the resident tissues. The main role of TRM cells is to provide superior protection against infection in extralymphoid tissues.[1][2]


Three cell surface markers that has been associated with TRM are CD69, CD49a, and CD103. CD69 suppresses response to the S1P chemoattractant from blood and lymph and prevents TRM cells from exiting peripheral tissue.[3][4] CD49a mediates tissue residency directly and marks cells with the most effector-like capabilities including IFN-gamma production and the ability to directly kill infected cells.[5][6] CD103 is expressed by many CD8+ TRM cells and rarely by CD4+ TRM cells, usually in conjunction with CD49a.[7] TRM cells have tissue residency-promoting transcriptional signature with features specific to individual tissues and features necessary for long-term survival in these tissues.[8]

  • Skin TRM: TRM cells in the skin express cutaneous lymphocyte antigen (CLA) and CCR8 which are skin homing antigens. They have also higher expression of markers CD103 and CD69, integrins, cytokine/growth factor receptors and signaling molecules CD49a, CD122 and PD-1.[9][10][11] On the other hand, they have downregulated chemokine receptors CCR7 and S1P1 which are important for recirculation. Skin TRM cells can survive in the skin for years depending upon IL-15 and fatty acid metabolism.[12][13][11] IL-15 and TGF-ß are required for differentiation of TRM cells in the skin in mouse models.[14][11]
  • Lung TRM: Lung TRM cells play important role in protection against respiratory infections. CD4+ follicular helper TRM cells promotes protection against virus infection by inducing B cells and CD8+ T cells. CD8+ TRM cells produce IFN-gamma which assists in viral clearance. TRM cells can also recruit neutrophils in case of bacterial infection. However, pathologic inflammation caused by lung TRM cells can lead to development of asthma or fibrosis. Human lung TRM CD4+ CD103+ cells express higher levels of CD103, CTLA4, KLRC1 and ICOS. CTLA4 is an inhibitor protein which role may lie in limitation of excessive effector and cytolytic activity which could lead to immune pathologies.[15] On the other hand, they have lower expression of S1P receptor S1PR1, homing receptor to lymph node CD62L, activation marker KLRG1, KLF2 and CCR7 than TEM in the blood.[16]
  • Other TRM: The majority of TRM express CD69 and CD103 markers. However, TRM without CD103 expression can be found in intestines, secondary lymphoid organs and liver. Moreover, TRM without both markers, CD69 and CD103, were found in substantial proportion in pancreas, salivary glands and female reproductive tract of mice.[17]


TRM cells develop from circulating effector memory T cell precursors in response to antigen. The main role in formation of TRM cells has CD103 and expression of this integrin is dependent on the cytokine TGF-β. CD8+ effector T cells that lack TGF-β fail to upregulate CD103, and subsequently do not differentiate into TRM cells. The important role in development of TRM cells have various cytokines that support TRM cell formation and survival. For example, homeostatic cytokine IL-15, pro-inflammatory cytokines such as IL-12 and IL-18, and barrier cytokines such as IL-33.[18][19][20] Also, generation of CD103+ TRM cells requires low expression of Eomes and T-bet transcription factors.[16]

Shortly after antigen-specific response in the non-lymphoid tissue, infected tissue is occupied by CD8+ effector-stage T cells (TEFF). These cells present early in the tissue have higher expression of some genes typical for TRM and at the peak of the T cell response, local T cell population expresses more than 90% of the TRM gene signature.[21] This shows that differentiation process of TRM cells starts early during immune response.[8]


TRM cells reside in many tissues that create barriers against outside environment and thus provide defense against repeatedly incoming pathogens. In the skin, lung, brain, and vagina TRM cells are required to provide immediate rapid control of re-infection. CD4+ TRM cells provide better protection against repeated infection with influenza in comparison with circulating memory CD4+ T cells.[22][23] Moreover, CD8+ TRM cells also play role in the protection against malignancies.[4] TRM cells express granzyme B which helps limit the spread of pathogens at the site of infection. Also, phenotypic and functional diversity is not only in TRM from different tissues, but it could be found in various TRM subsets within the same tissue. For example, CD49a distinguishes CD8+ TRM subsets with different functions. TRM cells positive for this marker produce perforin and IFNɤ. On the other side, TRM without CD49a expression produce IL-17.[24] IFNɤ production depends on the localization of TRM in the tissue niche. CD8+ TRM in mouse airways produce significant IFNɤ in comparison to parenchymal CD8+ TRM cells.[25][15] After reactivation, TRM cells undergo rapid proliferation in situ. Increase in TRM numbers after repeated exposure to antigens is not derived just from existing TRM, but circulating T cells contribute to the generation and higher numbers of TRM, too.[15] Also, not every TRM express CD69 and CD103 what support phenotypic heterogeneity of TRM cells.[17] TRM cells are able to activate innate and adaptive leukocytes to protect the host.[26][2][27][28] Cooperation of TRM cells with other memory T cell populations provide tissue surveillance and clearance of the infections.[29][30][11]

Potential of CD8+ TRM cells in cancer immunotherapy

Cytotoxic CD8+ T lymphocytes are able to recognize malignant cells. Production of neoantigens by tumour cells can lead to peptides which are presented to CD8+ T cells bound to MHC I. After antigen recognition, CD8+ T cells destroy tumor cells using IFN-ɤ, TNF-α, granzyme B and perforin. However, malignant cells can avoid this elimination by various mechanisms such as the loss of MHC I molecule, induction of anti-inflammatory tumor micro-environment, inhibition of T cell function, upregulation of ligands whose interactions with CD8+ T cell receptors results in their suppression etc. Immune checkpoint therapy and tumor-infiltrating lymphocytes (TIL) therapy are cancer immunotherapy strategies whose principle lies in suppression of tumor cell inhibitory pathways or in introduction of expanded CD8+ T cells. Whereas large fraction of TILs are TRM cells, they are candidates for solid cancer immunotherapy.[4]

TRM cells infiltrated in tumors have protective role and are associated with good clinical results in various cancer types, but not in pancreatic cancer. They have decreased expression of IFN-ɤ, TNF-α and IL-2 in comparison with circulating T cells in melanoma patients what suggest different mechanism for tumor growth control. Upregulation of granzyme A and granzyme B was found in TRM cells in lung carcinoma patients. However, in TRM cells are also upregulated immune checkpoint receptors. This suggests, that most of the tumor TRM show an exhausted phenotype which may be saved by immune checkpoint inhibitor therapies. Nonidentical tumors may contain different TRM populations.[4]

Role in disease pathogenesis

Autoreactive TRM cells and reduced ratio or activity of regulatory T cells (Tregs) which protects body from autoimmunity by securing self-tolerance may induce autoimmune diseases sucha as vitiligo, cutaneous lupus erythematosus, psoriasis, alopecia areata, cicatricial alopecia,multiple sclerosis, lupus nephritis, rheumatoid arthritis and autoimmune hepatitis.[11][31]


Vitiligo is an autoimmune skin disease with white spots phenotype. CD8+ T lymphocytes destroy melanocytes in some parts of the skin what manifest like white spots on the skin. Multiple genes as well as environment play role in developing vitiligo and migration of CD8+ T cells correlates with the state of disease. 80% of autoreactive CD8+ T cells which are specific towards melanocyte self-antigens express CD69 or CD69 and CD103 TRM markers. There is also higher number of CD49a+ CD8+ CD103+ T cells with cytotoxic potential in epiderma and derma of the vitiligo patients in comparison with healthy skin. Treatment of vitiligo lies in inhibition of JAK/STAT signaling pathway using JAK inhibitors. TRM cells have reduced IFNɤ production and white spots on skin disappear. However, the treatment can not be stopped, because white spots will appear again.[11]

Cutaneous Lupus Erythematosus (CLE)

CLE is another autoimmune skin disease with several subtypes. Common feature is interface dermatitis or inflammation at the dermal-epidermal junction. Again, contribution of genetic and environment factors lead to the development of CLE. It is not really clear what is the specificity of the T cell causing CLE in the skin, but some studies showed T cells reactive to nucleosomes/histones. Except aberrant T cell signaling which conduces to the pathogenesis of CLE, increased presence of TRM was also found in the skin of CLE patients refractory to antimalarials. Treatment lies in JAK/STAT inhibitors, but can not be stopped, because skin lessions will appear again.[11]


  1. ^ Schenkel JM, Masopust D (December 2014). "Tissue-resident memory T cells". Immunity. 41 (6): 886–97. doi:10.1016/j.immuni.2014.12.007. PMC 4276131. PMID 25526304.
  2. ^ a b Shin H, Iwasaki A (September 2013). "Tissue-resident memory T cells". Immunological Reviews. 255 (1): 165–81. doi:10.1111/imr.12087. PMC 3748618. PMID 23947354.
  3. ^ Mackay, Laura K.; Braun, Asolina; Macleod, Bethany L.; Collins, Nicholas; Tebartz, Christina; Bedoui, Sammy; Carbone, Francis R.; Gebhardt, Thomas (2015-03-01). "Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention". Journal of Immunology. 194 (5): 2059–2063. doi:10.4049/jimmunol.1402256. ISSN 1550-6606. PMID 25624457. S2CID 22798755.
  4. ^ a b c d Beumer-Chuwonpad, Ammarina; Taggenbrock, Renske L. R. E.; Ngo, T. An; van Gisbergen, Klaas P. J. M. (2021-08-28). "The Potential of Tissue-Resident Memory T Cells for Adoptive Immunotherapy against Cancer". Cells. 10 (9): 2234. doi:10.3390/cells10092234. ISSN 2073-4409. PMC 8465847. PMID 34571883.
  5. ^ Ray, Steven J.; Franki, Suzanne N.; Pierce, Robert H.; Dimitrova, Snezhana; Koteliansky, Victor; Sprague, Andrew G.; Doherty, Peter C.; de Fougerolles, Antonin R.; Topham, David J. (2004-02-17). "The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection". Immunity. 20 (2): 167–179. doi:10.1016/s1074-7613(04)00021-4. ISSN 1074-7613. PMID 14975239.
  6. ^ Reilly, Emma C.; Sportiello, Mike; Emo, Kris Lambert; Amitrano, Andrea M.; Jha, Rakshanda; Kumar, Ashwin B. R.; Laniewski, Nathan G.; Yang, Hongmei; Kim, Minsoo; Topham, David J. (2021). "CD49a Identifies Polyfunctional Memory CD8 T Cell Subsets that Persist in the Lungs After Influenza Infection". Frontiers in Immunology. 12: 728669. doi:10.3389/fimmu.2021.728669. ISSN 1664-3224. PMC 8462271. PMID 34566986.
  7. ^ Kumar BV, Ma W, Miron M, Granot T, Guyer RS, Carpenter DJ, et al. (September 2017). "Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites". Cell Reports. 20 (12): 2921–2934. doi:10.1016/j.celrep.2017.08.078. PMC 5646692. PMID 28930685.
  8. ^ a b Kok, Lianne; Masopust, David; Schumacher, Ton N. (2021-09-03). "The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues". Nature Reviews. Immunology. 22 (5): 283–293. doi:10.1038/s41577-021-00590-3. ISSN 1474-1741. PMC 8415193. PMID 34480118.
  9. ^ Weisberg, Stuart P.; Carpenter, Dustin J.; Chait, Michael; Dogra, Pranay; Gartrell-Corrado, Robyn D.; Chen, Andrew X.; Campbell, Sean; Liu, Wei; Saraf, Pooja; Snyder, Mark E.; Kubota, Masaru (2019-12-17). "Tissue-Resident Memory T Cells Mediate Immune Homeostasis in the Human Pancreas through the PD-1/PD-L1 Pathway". Cell Reports. 29 (12): 3916–3932.e5. doi:10.1016/j.celrep.2019.11.056. ISSN 2211-1247. PMC 6939378. PMID 31851923.
  10. ^ Sathaliyawala, Taheri; Kubota, Masaru; Yudanin, Naomi; Turner, Damian; Camp, Philip; Thome, Joseph J. C.; Bickham, Kara L.; Lerner, Harvey; Goldstein, Michael; Sykes, Megan; Kato, Tomoaki (2013-01-24). "Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets". Immunity. 38 (1): 187–197. doi:10.1016/j.immuni.2012.09.020. ISSN 1097-4180. PMC 3557604. PMID 23260195.
  11. ^ a b c d e f g Ryan, Grace E.; Harris, John E.; Richmond, Jillian M. (2021). "Resident Memory T Cells in Autoimmune Skin Diseases". Frontiers in Immunology. 12: 652191. doi:10.3389/fimmu.2021.652191. ISSN 1664-3224. PMC 8128248. PMID 34012438.
  12. ^ Richmond, Jillian M.; Strassner, James P.; Zapata, Lucio; Garg, Madhuri; Riding, Rebecca L.; Refat, Maggi A.; Fan, Xueli; Azzolino, Vincent; Tovar-Garza, Andrea; Tsurushita, Naoya; Pandya, Amit G. (2018-07-18). "Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo". Science Translational Medicine. 10 (450): eaam7710. doi:10.1126/scitranslmed.aam7710. ISSN 1946-6242. PMC 6495055. PMID 30021889.
  13. ^ Pan, Youdong; Tian, Tian; Park, Chang Ook; Lofftus, Serena Y.; Mei, Shenglin; Liu, Xing; Luo, Chi; O'Malley, John T.; Gehad, Ahmed; Teague, Jessica E.; Divito, Sherrie J. (2017-03-09). "Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism". Nature. 543 (7644): 252–256. Bibcode:2017Natur.543..252P. doi:10.1038/nature21379. ISSN 1476-4687. PMC 5509051. PMID 28219080.
  14. ^ Mackay, Laura K.; Rahimpour, Azad; Ma, Joel Z.; Collins, Nicholas; Stock, Angus T.; Hafon, Ming-Li; Vega-Ramos, Javier; Lauzurica, Pilar; Mueller, Scott N.; Stefanovic, Tijana; Tscharke, David C. (December 2013). "The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin". Nature Immunology. 14 (12): 1294–1301. doi:10.1038/ni.2744. hdl:1885/12900. ISSN 1529-2916. PMID 24162776. S2CID 32642573.
  15. ^ a b c Paik, Daniel H.; Farber, Donna L. (February 2021). "Anti-viral protective capacity of tissue resident memory T cells". Current Opinion in Virology. 46: 20–26. doi:10.1016/j.coviro.2020.09.006. ISSN 1879-6265. PMC 7979430. PMID 33130326.
  16. ^ a b Yuan, Rui; Yu, Jiang; Jiao, Ziqiao; Li, Jinfei; Wu, Fang; Yan, Rongkai; Huang, Xiaojie; Chen, Chen (2021). "The Roles of Tissue-Resident Memory T Cells in Lung Diseases". Frontiers in Immunology. 12: 710375. doi:10.3389/fimmu.2021.710375. ISSN 1664-3224. PMC 8542931. PMID 34707601.
  17. ^ a b Mueller, Scott N.; Mackay, Laura K. (February 2016). "Tissue-resident memory T cells: local specialists in immune defence". Nature Reviews. Immunology. 16 (2): 79–89. doi:10.1038/nri.2015.3. ISSN 1474-1741. PMID 26688350. S2CID 3155731.
  18. ^ Shin H (February 2018). "Formation and function of tissue-resident memory T cells during viral infection". Current Opinion in Virology. 28: 61–67. doi:10.1016/j.coviro.2017.11.001. PMID 29175730.
  19. ^ Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, et al. (December 2013). "The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin". Nature Immunology. 14 (12): 1294–301. doi:10.1038/ni.2744. hdl:1885/12900. PMID 24162776. S2CID 32642573.
  20. ^ Casey KA, Fraser KA, Schenkel JM, Moran A, Abt MC, Beura LK, et al. (May 2012). "Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues". Journal of Immunology. 188 (10): 4866–75. doi:10.4049/jimmunol.1200402. PMC 3345065. PMID 22504644.
  21. ^ Milner, J. Justin; Toma, Clara; Yu, Bingfei; Zhang, Kai; Omilusik, Kyla; Phan, Anthony T.; Wang, Dapeng; Getzler, Adam J.; Nguyen, Toan; Crotty, Shane; Wang, Wei (2017-12-14). "Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours". Nature. 552 (7684): 253–257. Bibcode:2017Natur.552..253M. doi:10.1038/nature24993. ISSN 1476-4687. PMC 5747964. PMID 29211713.
  22. ^ Teijaro, John R.; Turner, Damian; Pham, Quynh; Wherry, E. John; Lefrançois, Leo; Farber, Donna L. (2011-12-01). "Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection". Journal of Immunology. 187 (11): 5510–5514. doi:10.4049/jimmunol.1102243. ISSN 1550-6606. PMC 3221837. PMID 22058417.
  23. ^ Raphael, Itay; Joern, Rachel R.; Forsthuber, Thomas G. (2020-02-25). "Memory CD4+ T Cells in Immunity and Autoimmune Diseases". Cells. 9 (3): E531. doi:10.3390/cells9030531. ISSN 2073-4409. PMC 7140455. PMID 32106536.
  24. ^ Wu H, Liao W, Li Q, Long H, Yin H, Zhao M, Chan V, Lau CS, Lu Q (July 2018). "Pathogenic role of tissue-resident memory T cells in autoimmune diseases". Autoimmunity Reviews. 17 (9): 906–911. doi:10.1016/j.autrev.2018.03.014. PMID 30005862. S2CID 51625032.
  25. ^ McMaster, Sean R.; Wilson, Jarad J.; Wang, Hong; Kohlmeier, Jacob E. (2015-07-01). "Airway-Resident Memory CD8 T Cells Provide Antigen-Specific Protection against Respiratory Virus Challenge through Rapid IFN-γ Production". Journal of Immunology. 195 (1): 203–209. doi:10.4049/jimmunol.1402975. ISSN 1550-6606. PMC 4475417. PMID 26026054.
  26. ^ Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR (May 2009). "Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus". Nature Immunology. 10 (5): 524–30. doi:10.1038/ni.1718. PMID 19305395. S2CID 24388.
  27. ^ Wakim LM, Woodward-Davis A, Bevan MJ (October 2010). "Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence". Proceedings of the National Academy of Sciences of the United States of America. 107 (42): 17872–9. doi:10.1073/pnas.1010201107. PMC 2964240. PMID 20923878.
  28. ^ Ariotti S, Hogenbirk MA, Dijkgraaf FE, Visser LL, Hoekstra ME, Song JY, et al. (October 2014). "T cell memory. Skin-resident memory CD8⁺ T cells trigger a state of tissue-wide pathogen alert". Science. 346 (6205): 101–5. doi:10.1126/science.1254803. PMID 25278612. S2CID 37918023.
  29. ^ Richmond, Jillian M.; Strassner, James P.; Rashighi, Mehdi; Agarwal, Priti; Garg, Madhuri; Essien, Kingsley I.; Pell, Lila S.; Harris, John E. (April 2019). "Resident Memory and Recirculating Memory T Cells Cooperate to Maintain Disease in a Mouse Model of Vitiligo". The Journal of Investigative Dermatology. 139 (4): 769–778. doi:10.1016/j.jid.2018.10.032. ISSN 1523-1747. PMC 6431571. PMID 30423329.
  30. ^ Watanabe, Rei; Gehad, Ahmed; Yang, Chao; Scott, Laura L.; Teague, Jessica E.; Schlapbach, Christoph; Elco, Christopher P.; Huang, Victor; Matos, Tiago R.; Kupper, Thomas S.; Clark, Rachael A. (2015-03-18). "Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells". Science Translational Medicine. 7 (279): 279ra39. doi:10.1126/scitranslmed.3010302. ISSN 1946-6242. PMC 4425193. PMID 25787765.
  31. ^ Clark RA (January 2015). "Resident memory T cells in human health and disease". Science Translational Medicine. 7 (269): 269rv1. doi:10.1126/scitranslmed.3010641. PMC 4425129. PMID 25568072.
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Tissue-resident memory T cell
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