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 interferon-driven, anti-viral innate response critical to GTAU and developing robust adaptive immunity compared to adults and the elderly.
“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
The Introduction (page not provided) says naïve T cells protect against pathogens in early life and that T-cell functionality declines in later life, supporting an age-related difference in adaptive immunity. It does not establish that younger patients mount stronger adaptive responses than adults, or address an interferon-driven innate response or GTAU. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTrm do not express other putative activation markers, such as CD25, CD137, CD38, or HLA-DR.
“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]
The section “Tissue resident memory T (Trm) cells” says that CD69+ memory T cells in human tissues do not exhibit activation features such as HLA-DR, CD38, or CD25 expression. It does not address CD137, so the full list of markers attributed to this source is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTregs are present throughout the human body and their abundance in circulation and tissues is age dependent.
“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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STUDIES ON THE ROLE OF THE THYMUS IN IMMUNOBIOLOGY
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A guide to cancer immunotherapy: from T cell basic science to clinical practice
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“Interaction between CAFs and T lymphocytes T lymphocytes play a key role in modulating the adaptive immune response, and they comprise different subpopulations, such as Treg cells, helper T (Th) cells and cytotoxic T lymphocytes (CTLs) [206].”
BackgroundSingle-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment
Azizi, E., Carr, A. J., Plitas, G., Cornish, A. E., Konopacki, C., Prabhakaran, S., Nainys, J., Wu, K., Kiseliovas, V., Setty, M., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.060 · Cited by 1,976 · see citing works
Cross-tissue immune cell analysis reveals tissue-specific features in humans
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“This may be a resident population more prevalent in lymphoid sites (16).”
BackgroundGuidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
Cossarizza, A., Chang, H., Radbruch, A., Acs, A., Adam, D., Adam‐Klages, S., Agace, W. W., Aghaeepour, N., Akdiş, M., Allez, M., et al. (2019) · European Journal of Immunology · doi:10.1002/eji.201970107 · Cited by 982 · see citing works
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Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host’s Response to Pathogens
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Self-citationDevelopmental cell programs are co-opted in inflammatory skin disease
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
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The decisive early phase of bone regeneration
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RNA modifications: importance in immune cell biology and related diseases
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“ROLES OF RNA MODIFICATION IN IMMUNE CELL BIOLOGY RNA modifications and T lymphocytes T lymphocytes originate from bone marrow progenitors, mature in the thymus, and are transported to the periphery to fulfill immune functions after activation, proliferation, and differentiation.(304,305) The m(5)C methyltransferase NS…”
BackgroundSzabo, P. A., Dogra, P., Gray, J. I., Wells, S. B., Connors, T. J., Weisberg, S. P., Krupska, I., Matsumoto, R., Poon, M. M. L., Idzikowski, E., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.03.005 · Cited by 371 · see citing works
“In adult lungs, TRMs are the predominant T cell subset and persist in stable frequencies throughout many decades of life (Kumar et al., 2018; Thome et al., 2014), suggesting a crucial role in protection to respiratory pathogens.”
Self-citationLocal and systemic responses to SARS-CoV-2 infection in children and adults
Yoshida, M., Worlock, K. B., Huang, N., Lindeboom, R. G. H., Butler, C. R., Kumasaka, N., Dominguez Conde, C., Mamanova, L., Bolt, L., Richardson, L., et al. (2022) · Nature · doi:10.1038/s41586-021-04345-x · Cited by 365 · see citing works
CD4 T Helper Cell Subsets and Related Human Immunological Disorders
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“CD4 T cells originate from common lymphoid progenitors in the bone marrow, develop in the thymus, and execute their functions mainly in peripheral tissues and various lymphoid organs [3].”
BackgroundMetabolism as a guiding force for immunity
Jung, J., Zeng, H., & Horng, T. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0217-x · Cited by 345 · see citing works
Cancer vaccines: Building a bridge over troubled waters
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Microbial exposure during early human development primes fetal immune cells
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Emerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297 · see citing works
Estrogen Receptor Signaling in the Immune System
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“On the other side, CTLs are involved in effector cytotoxic functions [170].”
BackgroundT cells and the skin: from protective immunity to inflammatory skin disorders
Ho, A. W., & Kupper, T. S. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0162-3 · Cited by 241 · see citing works
Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human
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Memory CD4+ T Cells in Immunity and Autoimmune Diseases
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“An additional layer of complexity is added by the different memory CD4+ T cell subsets generated during the primary immune response [3,5].”
BackgroundTissue-resident memory T cells in tumor immunity and immunotherapy
Okła, K., Färber, D. L., & Zou, W. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20201605 · Cited by 230 · see citing works
SARS-CoV-2 infection generates tissue-localized immunological memory in humans
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“Each tissue had a distinct T cell subset composition that is conserved between individuals as we previously determined (26, 35, 42); T cell phenotypes for each site and for SARS-CoV-2–specific T cells are shown in representative flow cytometry plots (Fig.”
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BackgroundTissue-Resident Memory T Cells in Cancer Immunosurveillance
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“There are different subtypes, including Treg cells, helper T (Th) cells, and cytotoxic T lymphocytes (CTLs) [282].”
Tissue-resident immune cells in humans
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“CD45RACCR7 cells represent naive T cells, CD45RA(2)CCR7 cells represent central memoryTcells,CD45RA(2)CCR7(2)cells representT-effector/ effector memory T cells, and CD45RACCR7(2) cells represent terminally differentiated effector memory CD45RA T cells (TEMRAs) (45, 46).”
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“A pathogenactivated APC will subsequently travel to secondary lymphoid tissues, such as lymph nodes [178].”
BackgroundACE2-independent infection of T lymphocytes by SARS-CoV-2
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“Armed T cells play a pivotal role against pathogen infection.(10) As shown in our data, these T cells are likely to be targets of SARS-CoV-2 infection and undergo apoptosis in the HIF-1a-dependent pathway.”
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BackgroundGlycans as Key Checkpoints of T Cell Activity and Function
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“Lymphoid progenitors from the bone marrow enter into the cortical tissue of the thymus, where they start to expand and develop (9, 10).”
BackgroundGenetic engineering of T cells for immunotherapy
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“T lymphocytes consist of different subpopulations, such as Treg cells, T helper (Th) cells and cytotoxic T lymphocytes (CTL) [134].”
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“Yet, in humans, more pulmonary-resident CD8+ T cells are seen in advanced age (32).”
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“The thymus is the primary site of T cell differentiation into which T progenitor cells migrate from the bone marrow and undergo TCR rearrangement, giving rise to the two major subtypes of T cells: helper and regulatory (CD4) or cytotoxic (CD8) T cells (81).”
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“Activated T cells proliferate, and further differentiate into effector and memory subsets [37].”
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Prognostic and therapeutic role of tumor-infiltrating lymphocyte subtypes in breast cancer
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“In humans, populations of TRMs constitute the majority of T cells throughout the body and are present in constant frequencies over many decades of human life (Kumar et al., 2018a; Senda et al., 2019; Thome et al., 2014).”
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“T cells, through their diverse range of antigen receptors [T-cell receptors (TCRs)], recognize pathogenic or tumor-derived antigens and develop antigen-specific memory or tolerance (77).”
BackgroundIn Vivo T Cell-Targeting Nanoparticle Drug Delivery Systems: Considerations for Rational Design
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EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity
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Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span
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“Tissue immune responses in adults are rather mediated by adaptive TRM, which are predominant T cell populations in human mucosal and barrier sites ( 41 , 43 , 80 , 81 ).”
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“These include, T helper (Th)1, that protect intracellular pathogens Th2, and Th17 which target extracellular pathogens, regulatory T cells which help maintain self-tolerance and the follicular helper T cells (TFH) that assist B cells for antibody production [162].”
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- 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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