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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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“…initiated by the interaction between the T cell receptor (TCR) and peptide-bound major histocompatibility complex (pMHC), whereas the second is generated by speci fi c cognate interactions through adhesion molecules of T cells and antigen-presenting cells, such as CD28/CD80/CD86 interaction [2 – 4].”
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“In addition to facilitating adaptive immune responses, T cells are implicated in many inflammatory and autoimmune diseases (15, 16).”
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“…2 + ) channels, leading to a reduction in neuronal hyperexcitability and an increase in the levels of gamma-aminobutyric acid (GABA). mice with NP. 41 The efficacy of pregabalin and another GABA analog, gabapentin, was established in a separate research study conducted by Surcheva et al. (2017),…”
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“There are known differences in lymphoid development between human and mouse that may explain this discrepancy, but further investigations will be needed to fully understand the impact of DNMT3A loss on T-cell development.(30) Lower CD4/CD8 ratios have been associated with altered immune responses and inflammation; per…”
BackgroundThe Unusual Immune System of the Naked Mole-Rat
Lin, T., & Buffenstein, R. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-65943-1_12 · Cited by 23
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“Stimulation of the T cell receptor (TCR) and its co-stimulatory molecule, CD28, initiates a transcriptional program in naïve T cells that leads to activation, expansion, and differentiation into specialized CD4 helper and CD8 cytotoxic T cells 1,2 .”
PAD4 inhibition impacts immune responses in SARS-CoV-2 infection
Bonilha, C. S., Veras, F. P., Ramos, A. D. S., Gomes, G. F., Lemes, R. M. R., Arruda, E., Alves-Filho, J. C., Cunha, T. M., & Cunha, F. Q. (2025) · Mucosal Immunology · doi:10.1016/j.mucimm.2025.04.006 · Cited by 23
Evaluation of ultra-low input RNA sequencing for the study of human T cell transcriptome
Wang, J., Rieder, S. A., Wu, J., Hayes, S., Halpin, R., Reyes, M. D. L., Shrestha, Y., Kolbeck, R., & Raja, R. G. (2019) · Scientific Reports · doi:10.1038/s41598-019-44902-z · Cited by 23
The immunopathobiology of T cells in stress condition: a review
Khedri, M., Samei, A., Fasihi‐Ramandi, M., & Taheri, R. A. (2020) · Cell Stress and Chaperones · doi:10.1007/s12192-020-01105-0 · Cited by 24
Levite, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.617658 · Cited by 23
Physiological Functions of Mcl-1: Insights From Genetic Mouse Models
Chin, H. S., & Fu, N. Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.704547 · Cited by 22
“This in turn either neutralizes Bcl2 like pro-survival proteins, releasing Bax and Bak, or directly activates Bax and Bak (Letai et al., 2002; Kuwana et al., 2005).”
BackgroundA Darwinian perspective on tumor immune evasion
Puleo, J. I., & Polyák, K. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188671 · Cited by 23
Wu, H., Li, W., Hao, M., Wang, Y., Xue, L., Ju, C., & Zhang, C. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114380 · Cited by 23
Metabolic regulation of T cell development
Zhang, M., Lin, X., Zhou, Y., Li, X., Zhou, Z., Love, P. E., Huang, J., & Zhao, B. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.946119 · Cited by 28
Immune dysregulation and RNA N6 ‐methyladenosine modification in sepsis
Chen, H., Zhang, X., Su, H., Zeng, J., Chan, H., Li, Q., Liu, X., Zhang, L., Wu, W. K. K., Chan, M. T. V., et al. (2022) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1764 · Cited by 25
“After receiving appropriate antigenic and co-stimulatory signals, naive T cells undergo clonal expansion, culminating in a higher frequency of effector T cells including CD4+ and CD8+ T cells to eliminate pathogens invasion (Kumar et al., 2018).”
BackgroundLocal γδ T cells: translating promise to practice in cancer immunotherapy
Zlatareva, I., & Wu, Y. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02303-0 · Cited by 25
“, CD49a, CD103) [30, 31, 43] similar to tissue-resident memory (TRM) αβ T cell counterparts [83].”
BackgroundSnyder, M. E., Anderson, M. R., Benvenuto, L. J., Sutton, R. M., Bondonese, A., Koshy, R., Burke, R., Clifford, S., Craig, A., Iasella, C. J., et al. (2023) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2023.08.001 · Cited by 24
Mahajan, S., Alexander, A., Koenig, Z., Saba, N., Prasanphanich, N. S., Hildeman, D. A., Chougnet, C. A., DeFranco, E., Andorf, S., & Tilburgs, T. (2023) · JCI Insight · doi:10.1172/jci.insight.171806 · Cited by 23
“In humans, tissue-resident CCR7–CD45RA+ Teff and Trm populations were also shown to be increased in healthy mucosal tissues compared with blood and their proportions were shown to change, depending on donor age (56).”
Ouyang, Y., Gu, Y., Zhang, X., Huang, Y., Wei, X., Tang, F., & Zhang, S. (2024) · BMC Cancer · doi:10.1186/s12885-024-12025-y · Cited by 25
“Treg cells maintain immune self-tolerance and inhibit anti-cancer immunity [33], while CD8 + T cells are cytotoxic T lymphocytes that kill tumor cells [34].”
BackgroundKato, A., Takaori‐Kondo, A., Minato, N., & Hamazaki, Y. (2018) · European Journal of Immunology · doi:10.1002/eji.201747431 · Cited by 23
Mijnheer, G., & van Wijk, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00940 · Cited by 24
Roy, U., & Raghavan, S. C. (2021) · International Journal of Cancer · doi:10.1002/ijc.33527 · Cited by 26
Zhang, S., Chen, J., Cheng, F., & Fang, Z. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413722 · Cited by 23
Interaction of low-density neutrophils with other immune cells in the mechanism of inflammation
Fu, Y., Wen, Z., & Fan, J. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01187-5 · Cited by 25
“Their role is to orchestrate cell-mediated immune responses to maintain host health and prevent various diseases (Kumar et al. 2018).”
Recent research progress and clinical status of immunotherapy for colorectal cancer
Huo, Z., Liu, G., & Li, J. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.06.089 · Cited by 27
“CD4+ and CD8+ T cells, key components involved in anti-tumor immunity, interact with tumor antigens to regulate immune responses through diverse inhibitory and costimulatory signals [26,27].”
Deng, S., Chen, Z., & Shi, Y. (2025) · Cell & Bioscience · doi:10.1186/s13578-025-01486-8 · Cited by 28
“T lymphocytes, or T cells, are derived from progenitors in the bone marrow, which then travel to the thymus for maturation and selection before being released into the peripheral circulation [136].”
Toll-Like Receptor 2 Expression as a New Hallmark of Advanced Endometriosis
Sobstyl, M., Niedźwiedzka‐Rystwej, P., Grywalska, E., Korona‐Głowniak, I., Sobstyl, A., Bednarek, W., & Roliński, J. (2020) · Cells · doi:10.3390/cells9081813 · Cited by 24
“Mainly, T helper cells (Th) and T regulatory cells (Tregs) are involved, while Th1 are known for their pro-inflammatory actions, and Th2 are rather anti-inflammatory [22].”
BackgroundKrishnan, S., O’Boyle, C., Smith, C. J., Hulme, S., Allan, S. M., Grainger, J. R., & Lawrence, C. B. (2020) · Clinical & Experimental Immunology · doi:10.1111/cei.13551 · Cited by 24
Organized Chaos: Deciphering Immune Cell Heterogeneity’s Role in Inflammation in the Heart
Corker, A., Neff, L. S., Broughton, P. X., Bradshaw, A. D., & DeLeon‐Pennell, K. Y. (2021) · Biomolecules · doi:10.3390/biom12010011 · Cited by 22
“T-cells are part of the adaptive immune system classified by the expression of CD3 and become activated by antigen presenting cells including dendritic cells and macrophages [76].”
BackgroundInfluentialLeveraging biomaterials for enhancing T cell immunotherapy
Liao, Z., Zhang, W., Zheng, H., Wang, Y., Yu, J., Li, H., & Gu, Z. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.02.023 · Cited by 22
The Molecular Role of Immune Cells in Dilated Cardiomyopathy
Wang, E., Zhou, R., Li, T., Hua, Y., Zhou, K., Li, Y., Luo, S., & An, Q. (2023) · Medicina · doi:10.3390/medicina59071246 · Cited by 24
“These types of T cells have distinctive developmental and regulatory pathways, and they play varied roles in immunity and diseases related to the immune system [91].”
BackgroundCRISPR, CAR-T, and NK: Current applications and future perspectives
Khoshandam, M., Soltaninejad, H., Hamidieh, A. A., & Hosseinkhani, S. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.101121 · Cited by 25
“113 TILs are resistant cells that attack tumors to kill cancerous cells.”
BackgroundGiansanti, M., Theinert, T., Boeing, S. K., Haas, D., Schlegel, P., Vacca, P., Nazio, F., & Caruana, I. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01893-w · Cited by 24
“Both T cell subsets help our body to defend against external pathogens, prevent cancer development and fight malignant cells once the immune surveillance is ineffective [8].”
BackgroundNano-Drug Delivery Systems Targeting CAFs: A Promising Treatment for Pancreatic Cancer
Wang, M., Xue, W., Yuan, H., Wang, Z., & Yu, L. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s451151 · Cited by 24
“93 Extensive research has elucidated the role of CAFs in modulating T cell activity and function.”
Background3D genome organization during lymphocyte development and activation
Schoonhoven, A. O.-V., Huylebroeck, D., Hendriks, R. W., & Stadhouders, R. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz030 · Cited by 24
Exploring the depths of IgG4: insights into autoimmunity and novel treatments
Ünlü, S., Navarro, B. G. S., Çakan, E., Berchtold, D., Hanna, R. M., Vural, S., Vural, A., Meisel, A., & Fichtner, M. L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1346671 · Cited by 23
Shah, P. N., Romar, G. A., Manukyan, A., Ko, W.-C. C., Hsieh, P., Velasquez, G. A., Schunkert, E. M., Fu, X., Guleria, I., Bronson, R. T., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci178253 · Cited by 23
“Though we relied on classical definitions of T cell subsets (28, 29, 32, 69, 70), current definitions are likely imperfect, (71) particularly during active inflammation, as T cell subsets may be more plastic than commonly credited (71).”
CAR T Cell Therapy for Rheumatoid Arthritis
Freeley, M. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09113-7 · Cited by 25
“…CD4 + helper T cells, CD8 + cytotoxic T cells, naïve, effector, memory cells central, effector, stem cell-like subtypes or regulatory T cells [ 19]), while the CAR itself can be engineered to target defined sub - sets of pathogenic cells including antigen-specific B cells or T cells and thus…”
Jo, N., Zhang, R., Ueno, H., Yamamoto, T., Weiskopf, D., Nagao, M., Yamanaka, S., & Hamazaki, Y. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.719342 · Cited by 20
“Considering that T cell composition dramatically changes throughout life (Kumar et al., 2018), the number or functionalities of pre-existing SARS-CoV-2-reactive T cells with the MP as well as naïve phenotype (NP) could change with age, thus explaining the age-related differences in COVID19 severity.”
BackgroundPathogenic and Potential Therapeutic Roles of Exosomes Derived From Immune Cells in Liver Diseases
Zhou, L., Shen, M., Fan, X., Liu, Y., & Yang, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.810300 · Cited by 22
Genetic Landscape of Peripheral T-Cell Lymphoma
Hathuc, V. M., & Kreisel, F. H. C. (2022) · Life · doi:10.3390/life12030410 · Cited by 21
“After thymic maturation, naive CD4 positive, and CD8 positive T-lymphocytes then circulate in peripheral blood and the lymphatic system to further differentiate into specialized CD4 and CD8 T-Cell subsets [1].”
BackgroundAndonian, B. J., Koss, A., Koves, T. R., Hauser, E. R., Hubal, M. J., POBER, D. M., Lord, J. M., MacIver, N. J., Clair, E. W. S., Muoio, D. M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-11458-4 · Cited by 28
Considerations of CD8+ T Cells for Optimized Vaccine Strategies Against Respiratory Viruses
Hirai, T., & Yoshioka, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.918611 · Cited by 21
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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