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Human T Cell Development, Localization, and Function throughout Life
Open accessAbstract
Throughout life, T cells coordinate multiple aspects of adaptive immunity, including responses to pathogens, allergens, and tumors. In mouse models, the role of T cells is studied in the context of a specific type of pathogen, antigen, or disease condition over a limited time frame, whereas in humans, T cells control multiple insults simultaneously throughout the body and maintain immune homeostasis over decades. In this review, we discuss how human T cells develop and provide essential immune protection at different life stages and highlight tissue localization and subset delineation as key determinants of the T cell functional role in immune responses. We also discuss how anatomic compartments undergo distinct age-associated changes in T cell subset composition and function over a lifetime. It is important to consider age and tissue influences on human T cells when developing targeted strategies to modulate T cell-mediated immunity in vaccines and immunotherapies.
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“Younger patients may be more capable of mounting the interferondriven, anti-viral innate response critical to GTAU and developing robust adaptive immunity compared to adults and the elderly (Kumar et al., 2018; Yoshida et al., 2022).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Kumar et al., 2018
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“Trm do not express other putative activation markers, such as CD25, CD137, CD38, or HLA-DR [244, 253, 258, 264].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [264]
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“Tregs are present throughout the human body and their abundance in circulation and tissues is age dependent [264, 359].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [264]
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Cytotoxic T Cells: Kill, Memorize, and Mask to Maintain Immune Homeostasis
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“This is because the changes associated with immunosenescence, such as increased inflammation and decreased T lymphocytes functionality, contribute to immune system dysregulation [19,26].”
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“However, these antigen-inexperienced cells continue to mature extrathymically, rapidly differentiating into mature naive T cells (MNTs) [6–10].”
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“T cells play a crucial role in recognizing diverse antigens derived from pathogens, tumors, and the environment while maintaining immune memory and self-tolerance (Kumar et al. 2018, Belk et al. 2022).”
Ge, T., He, G., Cui, Q., Wang, S., Wang, Z., Xie, Y., Tian, Y., Zhou, J., Li, W., Wang, B., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1599515 · Cited by 7
Kilgore, M. D., Xiu, Y., Jiang, Y., Wang, Y., Shi, M., Zhou, D., Sein, T. Y., Vodovoz, S. J., Wang, D., Dumont, A. S., et al. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70580 · Cited by 7
“T cells are a unique population of adaptive immune cells that are derived from lymphoid progenitor cells and mature into specific functional subsets in the thymus during development before migrating to peripheral storage compartments [18].”
Jin, C., Ma, B., Zhong, C., Jia, L., Yang, J., Wang, W., Liu, J., Zhou, Y., Zhu, R., Yang, B., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115585 · Cited by 7
Pu, H., Ding, L., Jiang, P., Li, G., Wang, W., Jiang, J., & Gan, X. (2025) · Biomedicines · doi:10.3390/biomedicines13102426 · Cited by 7
“The bone marrow microenvironment supports the development of B and T cells by secreting factors such as IL-7, SCF, and CXCL12, and providing vascular and stromal support, thus ensuring the functional integrity of adaptive immunity [15].”
van der Vegt, S. A., Wang, Y., Polonchuk, L., Wang, K., Waters, S. L., & Baker, R. E. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.966180 · Cited by 8
“T cell progenitors originate in the bone marrow and migrate to the thymus, where they mature (Kumar et al., 2018).”
BackgroundInfluentialMultifaceted roles of T cells in obesity and obesity‐related complications: A narrative review
Qi, X., Li, Z., Han, J., Liu, W., Xia, P., Cai, X., Liu, X., Liu, X., Zhang, J., & Yu, P. (2023) · Obesity Reviews · doi:10.1111/obr.13621 · Cited by 13
“double-positive T cells (CD4CD8).(9) Immediately, these doublepositive T cells form mature T cells, most commonly called CD4 T cells (containing Th cells and immunosuppressive Tregs) and CD8 cytotoxic T cells.”
BackgroundMechanism study of ubiquitination in T cell development and autoimmune disease
Yu, H., Yang, W., Cao, M., Lei, Q., Yuan, R., He, X., Cui, Y., Chen, X., Su, X., Zhuo, H., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1359933 · Cited by 7
Rengifo, T. P., Bishir, M., Huang, W., Snyder, M., & Chang, S. L. (2024) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.15292 · Cited by 6
fan, G., Yang, W., Wang, D., Xu, F., Wang, Y., Si, C., Zhai, Z., Li, Z., Wu, R., Cao, B., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e31733 · Cited by 7
The Pluripotent Path to Immunotherapy
Diop, M. P., & van der Stegen, S. J. C. (2024) · Experimental Hematology · doi:10.1016/j.exphem.2024.104648 · Cited by 10
Leveraging Immunotherapy with Nanomedicine
Mittelheisser, V., Banerjee, M., Pivot, X. B., Charbonnière, L. J., Goetz, J. G., & Detappe, A. (2020) · Advanced Therapeutics · doi:10.1002/adtp.202000134 · Cited by 6
Leaving no one behind: tracing every human thymocyte by single-cell RNA-sequencing
Deng, Y., Chen, H., Zeng, Y., Wang, K., Zhang, H., & Hu, H. (2021) · Seminars in Immunopathology · doi:10.1007/s00281-020-00834-9 · Cited by 7
Saranya, B., & Gowri, M. (2021) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2021.131674 · Cited by 7
Long, X., Luo, C., & Zhu, Z. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.919550 · Cited by 7
Li, J., Reinke, S., Yu, S., Schollmeyer, L., Liu, Y.-C., Wang, Z., Hardt, S., Hipfl, C., Hoffmann, U., Frischbutter, S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1004656 · Cited by 7
Paxbp1 is indispensable for the survival of CD4 and CD8 double-positive thymocytes
Li, W., Yang, Y., Liu, S., Zhang, D., Ren, X., Tang, M., Zhang, W., Chen, X., Huang, C., & Yu, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1183367 · Cited by 7
Characterizing the T Cell Repertoire in the Proximal Airway in Health and Disease
Clark, E. A., Talatala, E. R. R., Ye, W., Davis, R. J., Collins, S. L., Hillel, A. T., Ramirez-Solano, M. A., Sheng, Q., Wanjalla, C. N., Mallal, S. A., et al. (2023) · The Laryngoscope · doi:10.1002/lary.31088 · Cited by 7
“13 This speci fi cation is largely driven by the TCR expressed on the surface of each T cell.”
BackgroundGuo, K., Feng, X., Xu, L., Li, C., Ma, Y., & Peng, M. (2024) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2024-0371 · Cited by 7
Single-Cell RNA Sequencing Approaches for Tracing T Cell Development
Oh, S., Gray, D. H. D., & Chong, M. M. W. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100408 · Cited by 8
Canine memory T-cell subsets in health and disease
Bauman, A. B., Moeller, C. E., Soileau, A. M., Goodermuth, C. E., Costa, V. R., Schaumburg, J. C., Pucheu‐Haston, C. M., Welborn, N. D., Dehghanpir, S. D., Mitchell, M. A., et al. (2022) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2022.110401 · Cited by 7
Laranjeira, P., Rodrigues, T., Silva, A., Barbosa, P., Reis, T., Lopes, C., Pinho, A. C. O., Silva, S., Silva, I., Carvalho, A., et al. (2022) · Clinical and Experimental Medicine · doi:10.1007/s10238-022-00801-8 · Cited by 6
The pore conformation of lymphocyte perforinPreprint
Ivanova, M., Lukoyanova, N., Malhotra, S., Topf, M., Trapani, J. A., Voskoboinik, I., & Saibil, H. R. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.03.450947 · Cited by 7
Applying metabolic control strategies to engineered T cell cancer therapies
Fox, A., & Blazeck, J. (2024) · Metabolic Engineering · doi:10.1016/j.ymben.2024.10.009 · Cited by 7
Dai, Y., Dong, C., Wang, Z., Zhou, Y., Wang, Y., Hao, Y., Chen, P., Liang, C., & Li, G. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1482291 · Cited by 6
Epigenetic Regulation of B Cell Memory Formation: A Poised Model for B Cell Epigenetic Reprograming
Valverde-Hernandez, C. (2025) · Journal of Immunology Research · doi:10.1155/jimr/9328523 · Cited by 6
“To this end, T and B lymphocytes need to experience important genetic and epigenetic changes from precursor to effector lymphocyte states [2, 3].”
Frouard, J., Telwatte, S., Luo, X., Gill, N., Thomas, R., Arneson, D. V., Roychoudhury, P., Butte, A. J., Wong, J. K., Hoh, R., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68797-3 · Cited by 12
“Although it may seem perplexing that we observed active reservoir cells to preferentially reside among Tem, which are generally considered short-lived 82 , it is worth noting that long-lived Tem cells have been described in the context of viral infections 83 – 85 .”
Rudolph, M. E., McArthur, M. A., Magder, L. S., Barnes, R. S., Chen, W. H., & Sztein, M. B. (2019) · Clinical Immunology · doi:10.1016/j.clim.2019.04.002 · Cited by 6
Deciphering the Tumor–Immune–Microbe Interactions in HPV-Negative Head and Neck Cancer
Hu, M., Coleman, S. S., Fadlullah, M. Z. H., Spakowicz, D. J., Chung, C. H., & Tan, A. C. (2023) · Genes · doi:10.3390/genes14081599 · Cited by 6
“T cells are the main effector cells that contribute to the elimination of abnormal cells, such as neoplastic cells [83].”
BackgroundRios, L. E., Lokugamage, N., Choudhuri, S., Chowdhury, I. H., & Garg, N. J. (2023) · npj Vaccines · doi:10.1038/s41541-023-00782-z · Cited by 6
“Similarly, CD8 + T cells differentiate as mature effectors that release cytotoxic molecules and cytokines for pathogen control and as central memory cells to provide protection against future infections 37 .”
Song, W., Hu, J., Zhu, L., Chen, B., Li, L., Cui, X., Zhang, T., Miao, Y., Su, K., Liu, C., et al. (2024) · Food Science and Human Wellness · doi:10.26599/fshw.2024.9250040 · Cited by 9
Waheed, W., Bacopulos, A., Seyam, M., Kooperkamp, H. Z., Moin, M., Malik, T., & Tandan, R. (2024) · Mediastinum · doi:10.21037/med-23-43 · Cited by 8
Savvidis, S., Ragazzini, R., de Rafael, V. C., Hutchinson, J. C., Massimi, L., Vittoria, F. A., Campinoti, S., Partridge, T., Ogunbiyi, O. K., Atzeni, A., et al. (2024) · Communications Medicine · doi:10.1038/s43856-024-00623-7 · Cited by 6
“Speci fi cally, by GW 12-13 this organ starts producing T-cells (or thymic-dependent (T) lymphocytes, whose precursors originate from the bone marrow), which form part of the adaptive immune system, providing the body with cell-mediated immunity 10,11 .”
BackgroundHoerter, A., Petrucciani, A., Bonifacio, J. R., Arnett, E., Schlesinger, L. S., & Pienaar, E. (2025) · mSystems · doi:10.1128/msystems.01290-24 · Cited by 6
Kashkoulinejad-Kouhi, T. (2025) · Cytokine · doi:10.1016/j.cyto.2025.156914 · Cited by 6
Metadata
- Authors
- Kumar, B. V., Connors, T. J., & Farber, D. L.
- Affiliations
- Columbia University Irving Medical Center (US)
- ORCID
- Connors, Thomas J.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 48
- Issue
- 2
- Pages
- 202-213
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5826622
- OpenAlex
- W2789026035
- Cited by
- 1,257
- References
- 132
- Citations by year
- 2026: 100 · 2025: 181 · 2024: 213 · 2023: 207 · 2022: 233 · 2021: 171 · 2020: 85 · 2019: 47 · 2018: 19
- FWCI
- 8.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (AI106697, AI128949)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- T cell development, T cell localization, T cell subsets, immunosenescence, tissue localization, immune homeostasis, adaptive immunity, age-related changes, T cell immunity, vaccines, immunotherapy
- MeSH terms
- Animals, Humans, Immunologic Memory, T-Lymphocytes, Tissue Distribution, T-Lymphocyte Subsets, Lymphopoiesis, T-Lymphocytes, Regulatory, Adaptive Immunity
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