Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
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Volume 10 Number 1 2026
REVIEWS (Open Access)
Tissue-Resident Memory T Cells in Health and Disease: Emerging Regulators of Immunity
Siska Ferilda 1*, Zainab Nur-Eldeen Aziz 2, Basil O. Saleh 2
Integrative Biomedical Research 10 (1) 1-8 https://doi.org/10.25163/biomedical.10110888
Submitted: 25 May 2026 Revised: 10 July 2026 Accepted: 22 July 2026 Published: 24 July 2026
Abstract
Immunological memory has traditionally been described through two circulating T-cell subsets, central memory and effector memory, that continuously recirculate through blood and lymph. The discovery of a third, non-circulating lineage — tissue-resident memory T (TRM) cells — has reshaped this model, revealing a permanent cellular garrison embedded within barrier and non-barrier organs alike. We conducted a narrative, synthesis of peer-reviewed immunology literature, focused on TRM phenotype, transcriptional and metabolic regulation, organ-specific heterogeneity, disease pathogenicity, and emerging therapeutics. Synthesis across ten anatomical sites shows that TRM cells adopt markedly organ-specific retention markers, transcriptional circuits, and metabolic programs, while remaining unified by core Hobit/Blimp-1/Runx3-driven residency circuitry. Across ten autoimmune and inflammatory diseases, dysregulated TRM subsets form a stable, compartmentalized “lesion memory” that drives recurrent flares independent of systemic remission, and an emerging pipeline of IL-15/CD122 blockade, JAK inhibition, S1PR1 agonism, integrin blockade, and metabolic targeting is beginning to allow selective modulation of pathogenic TRM populations. TRM biology offers a mechanistically precise, tissue-targeted alternative to systemic immunosuppression, provided therapies can be designed to spare protective resident pools while silencing pathogenic ones.
Keywords: tissue-resident memory T cells; immunological memory; autoimmunity; lesion memory; CD103; IL-15; JAK inhibition; precision immunotherapy
References
Bankovich, A. J., Shiow, L. R., & Cyster, J. G. (2010). CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4. Journal of Biological Chemistry, 285(29), 22328–22337. https://doi.org/10.1074/jbc.M110.123299
Buggert, M., Vella, L. A., Nguyen, S., Wu, V. H., Chen, Z., Sekine, T., Perez-Potti, A., Cole, B., Jiang, S. Y., Anda, S., & Betts, M. R. (2020). The identity of human tissue-emigrant CD8+ T cells. Cell, 183(7), 1946–1961. https://doi.org/10.1016/j.cell.2020.11.019
Chang, M. H., Levescot, A., Nelson-Maney, N., Blaustein, R. B., Winden, K. D., Morris, A., Wactor, A., Balu, S., Grieshaber-Bouyer, R., Wei, K., & Wei, K. (2021). Arthritis flares mediated by tissue-resident memory T cells in the joint. Cell Reports, 37(4), 109902. https://doi.org/10.1016/j.celrep.2021.109902
Chen, L., & Shen, Z. (2020). Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders. Cellular & Molecular Immunology, 17(1), 64–75. https://doi.org/10.1038/s41423-019-0291-4
Cheng, L., & Becattini, S. (2022). Intestinal CD8+ tissue-resident memory T cells: From generation to function. European Journal of Immunology, 52(10), 1547–1560. https://doi.org/10.1002/eji.202149759
Cheuk, S., Schlums, H., Gallais Sérézal, I., Martini, E., Chiang, S. C., Marquardt, N., & Boniface, K. (2017). CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity, 46(2), 287–300. https://doi.org/10.1016/j.immuni.2017.01.009
Christo, S. N., Park, S. L., Mueller, S. N., & Mackay, L. K. (2024). The multifaceted role of tissue-resident memory T cells. Annual Review of Immunology, 42, 317–345. https://doi.org/10.1146/annurev-immunol-101320-020220
Chude, C. F., Uzonna, J. E., & Arsenio, J. (2025). Tissue resident memory cells: Friend or foe in chronic inflammation. Immunology, in press. https://doi.org/10.1111/imm.70024
Clark, R. A. (2015). Resident memory T cells in human health and disease. Science Translational Medicine, 7(269), 269rv1. https://doi.org/10.1126/scitranslmed.3009008
Erle, D. J., Briskin, M. J., Butcher, E. C., Garcia-Pardo, A., Lazarovits, A. I., & Tidswell, M. (1995). Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. Journal of Immunology, 153(2), 517–528.
Fonseca, R., Beura, L. K., Quarnstrom, C. F., Ghoneim, H. E., Fan, Y., Zebley, C. C., Scott, M. C., Fares-Frederickson, N., & Masopust, D. (2020). Developmental plasticity allows outside-in immune responses by resident memory T cells. Nature Immunology, 21(4), 412–421. https://doi.org/10.1038/s41590-020-0607-7
Frizzell, H., Fonseca, R., Christo, S. N., & Mackay, L. K. (2020). Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes. Science Immunology, 5(46), eaay9283. https://doi.org/10.1126/sciimmunol.aay9283
Gebhardt, T., & Mackay, L. K. (2012). Local immunity by tissue-resident CD8+ memory T cells. Frontiers in Immunology, 3, 340. https://doi.org/10.3389/fimmu.2012.00340
Gray, J. I., & Farber, D. L. (2022). Tissue-resident immune cells in humans. Annual Review of Immunology, 40, 195–220. https://doi.org/10.1146/annurev-immunol-093019-112809
Hogan, R. J., Usherwood, E. J., Zhong, W., Roberts, A. A., Dutton, R. W., Harmsen, A. G., & Woodland, D. L. (2001). Activated antigen-specific CD8+ T cells persist in the lungs following recovery from respiratory virus infections. Journal of Immunology, 166(3), 1813–1822. https://doi.org/10.4049/jimmunol.166.3.1813
Iijima, N. (2024). The emerging role of effector functions exerted by tissue-resident memory T cells. Oxford Open Immunology, 5(1), iqae006. https://doi.org/10.1093/oxfimm/iqae006
Kok, L., Masopust, D., & Schumacher, T. N. (2022). The precursors of CD8+ tissue resident memory T cells: From lymphoid organs to infected tissues. Nature Reviews Immunology, 22(5), 283–293. https://doi.org/10.1038/s41577-021-00590-3
Li, J., Xiao, C., Li, C., & He, J. (2025). Tissue-resident immune cells: From defining characteristics to roles in diseases. Signal Transduction and Targeted Therapy, 10, 12. https://doi.org/10.1038/s41392-024-02050-5
Liu, X., Peng, T., Xu, M., Lin, S., Hu, B., Chu, T., Liu, B., Xu, Y., Ding, W., Li, L., & Zheng, J. (2018). Molecular imaging reveals a high total body burden of tissue-resident memory T cells. bioRxiv.
Lyu, Y., Zhou, Y., & Shen, J. (2022). An overview of tissue-resident memory T cells in the intestine: From physiological functions to pathological mechanisms. Frontiers in Immunology, 13, 912393. https://doi.org/10.3389/fimmu.2022.912393
Mackay, L. K., Minnich, M., Kragten, N. A. M., Liao, Y., Nota, B., Seillet, C., Zaid, A., Man, K., Preston, S., Freestone, D., & Kallies, A. (2016). Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science, 352(6284), 459–463. https://doi.org/10.1126/science.aad2035
Mackay, L. K., Wynne-Jones, E., Freestone, D., Pellicci, D. G., Mielke, L. A., Newman, D. M., Braun, A., Masson, F., Kallies, A., Belz, G. T., & Carbone, F. R. (2015). T-box transcription factors combine with the cytokines TGF-beta and IL-15 to control tissue-resident memory T cell fate. Immunity, 43(6), 1101–1111. https://doi.org/10.1016/j.immuni.2015.11.008
Masopust, D., Vezys, V., Marzo, A. L., & Lefrançois, L. (2001). Preferential localization of effector memory cells in nonlymphoid tissue. Science, 291(5512), 2413–2417. https://doi.org/10.1126/science.1058867
Milner, J. J., Toma, C., Yu, B., Zhang, K., Omilusik, K., Phan, A. T., Wang, D., Getzler, A. J., Nguyen, T., Crotty, S., Wang, W., Pipkin, M. E., & Goldrath, A. W. (2017). Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature, 552(7684), 253–257. https://doi.org/10.1038/nature24993
Murakami, M. (2024). Tissue-resident memory T cells: Decoding intra-organ diversity with a gut perspective. Inflammation and Regeneration, 44, 19. https://doi.org/10.1186/s41232-024-00333-6
Pan, Y., Tian, T., Park, C. O., Lofftus, S. Y., Mei, S., Liu, X., Luo, C., O’Malley, J. T., Gehad, A., Teague, J. E., Divito, S. J., Fuhlbrigge, R., Puigserver, P., Krueger, J. G., Hotamisligil, G. S., Clark, R. A., & Kupper, T. S. (2017). Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature, 543(7644), 252–256. https://doi.org/10.1038/nature21379
Park, C. O., & Kupper, T. S. (2015). The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nature Medicine, 21(7), 688–697. https://doi.org/10.1038/nm.3883
Park, S. L., Buzzai, A., Rautela, J., Hor, J. L., Hochheiser, K., Effern, M., McBain, N., Wagner, T., Edwards, J., McConville, R., Wilmott, J. S., Scolyer, R. A., Tüting, T., Palendira, U., Gyorki, D., Mueller, S. N., Huntington, N. D., Bedoui, S., Hölzel, M., … Mackay, L. K. (2019). Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature, 565(7739), 366–371. https://doi.org/10.1038/s41586-018-0812-9
Sallusto, F., Lenig, D., Förster, R., Lipp, M., & Lanzavecchia, A. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature, 401(6754), 708–712. https://doi.org/10.1038/44385
Samat, A. A. K., van der Geest, J., Vastert, S. J., van Loosdregt, J., & van Wijk, F. (2021). Tissue-resident memory T cells in chronic inflammation—Local cells with systemic effects? Cells, 10(2), 409. https://doi.org/10.3390/cells10020409
Sasson, S. C., Gordon, C. L., Christo, S. N., Klenerman, P., & Mackay, L. K. (2020). Local heroes or villains: Tissue-resident memory T cells in human health and disease. Cellular & Molecular Immunology, 17(2), 113–122. https://doi.org/10.1038/s41423-019-0359-1
Schenkel, J. M., & Masopust, D. (2014). Tissue-resident memory T cells. Immunity, 41(6), 886–897. https://doi.org/10.1016/j.immuni.2014.12.007
Schenkel, J. M., Fraser, K. A., Beura, L. K., Pauken, K. E., Vezys, V., & Masopust, D. (2014). T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science, 346(6205), 98–101. https://doi.org/10.1126/science.1254536
Schenkel, J. M., Fraser, K. A., Vezys, V., & Masopust, D. (2013). Sensing and alarm function of resident memory CD8+ T cells. Nature Immunology, 14(5), 509–513. https://doi.org/10.1038/ni.2568
Shin, H., & Iwasaki, A. (2013). Tissue-resident memory T cells. Immunological Reviews, 255(1), 165–181. https://doi.org/10.1111/imr.12087
Takamura, S. (2018). Niches for the long-term maintenance of tissue-resident memory T cells. Frontiers in Immunology, 9, 1214. https://doi.org/10.3389/fimmu.2018.01214
Tian, Y., Zhang, J., Wu, L., Zhang, C., Zheng, F., Yang, Y., Lu, G., & Xie, D. (2025). Tissue-resident memory T cells in rheumatoid immune diseases: Pathogenic mechanisms and therapeutic strategies. Biomedicines, 13(12), 2945. https://doi.org/10.3390/biomedicines13122945
Topham, D. J., & Reilly, E. C. (2018). Tissue-resident memory CD8+ T cells: From phenotype to function. Frontiers in Immunology, 9, 515. https://doi.org/10.3389/fimmu.2018.00515
Xiao, Z.-J., & Sun, Z.-J. (2025). Tissue-resident memory T cells. Cancer Medicine, 14(1), e71429. https://doi.org/10.1002/cam4.71429
Xie, D., Lu, G., Mai, G., Guo, Q., & Xu, G. (2025). Tissue-resident memory T cells in diseases and therapeutic strategies. MedComm, 6, e70053. https://doi.org/10.1002/mco2.70053
Xu, L., Ye, L., & Huang, Q. (2025). Tissue-resident memory CD8+ T cells: Differentiation, phenotypic heterogeneity, biological function, disease, and therapy. MedComm, 6, e70132. https://doi.org/10.1002/mco2.70132
Yenyuwadee, S., Sanchez-Trincado Lopez, J. L., Shah, R., Rosato, P. C., & Boussiotis, V. A. (2022). The evolving role of tissue-resident memory T cells in infections and cancer. Science Advances, 8(33), eabo5871. https://doi.org/10.1126/sciadv.abo5871
Yokoi, T., Murakami, M., Kihara, T., Seno, H., & Arase, H. (2023). CD161+ CCR5+ CD4+ tissue-resident memory T cells drive pathology in Crohn’s disease. Mucosal Immunology, 16(4), 405–417.
Zhou, M., Guo, C., Li, X., Huang, Y., Li, M., Zhang, T., Zhao, S., Wang, S., Zhang, H., & Yang, N. (2020). JAK/STAT signaling controls the fate of CD8+CD103+ tissue-resident memory T cells in lupus nephritis. Journal of Autoimmunity, 109, 102424. https://doi.org/10.1016/j.jaut.2020.102424
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