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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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Citations
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“Human T cell subsets also follow a tissue-dependent pattern of distribution and maintenance, but unlike innate cells, tissue intrinsic subset composition exhibits age-associated changes, as reviewed elsewhere (Kumar et al., 2018).”
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BackgroundCharge-altering releasable transporters enhance mRNA delivery in vitro and exhibit in vivo tropism
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“Forexample, a comb-shaped polymer (CP-25-16) has been developed which transfects 25% of primary human T cells in vitro 27 (Fig.”
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“Our prior studies using these tissues reveal that T cell subset composition, phenotype, function, and transcriptome profiles are specific to the tissue and exhibit site-specific variations with age (Kumar et al., 2018).”
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“TRM are often defined by expression of the biomarkers CD69 and/or CD103, each thought to have a unique contribution toward establishing residency and displaying different expression patterns in human nonlymphoid tissues (16).”
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“T-cells, lymphocytes in the cell-mediated adaptive immune response, are involved in viral clearance and long-term antiviral immunity (184).”
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T-Cell Receptor Repertoire Sequencing and Its Applications: Focus on Infectious Diseases and Cancer
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“The entire amazingly broad and diverse assembly of TCR sequences, known as the TCR repertoire, is composed of naive T-cells, antigen-inexperienced cells shaped in the thymus, where new antigen specificities are introduced [20,21], and memory T-lymphocytes, antigen-experienced cells whose specificity depends on antigen…”
BackgroundLyu, Z., Xin, M., Oyston, D. R., Xue, T., Kang, H., Wang, X., Wang, Z., & Wang, Z. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155354 · Cited by 58
Innate Immunity and Biological Therapies for the Treatment of Sjögren’s Syndrome
Srivastava, A., & Makarenkova, H. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239172 · Cited by 61
“There are various types of T cells and they play different roles in the immune system [114].”
BackgroundImmunomodulatory potential of flavonoids for the treatment of autoimmune diseases and tumour
Han, L., Fu, Q., Deng, C., Luo, L., Xiang, T., & Zhao, H. (2021) · Scandinavian Journal of Immunology · doi:10.1111/sji.13106 · Cited by 63
Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease
Li, R., Tropea, T. F., Baratta, L. R., Zuroff, L. R., Diaz‐Ortiz, M. E., Zhang, B., Shinoda, K., Rezk, A., Alcalay, R. N., Chen‐Plotkin, A. S., et al. (2021) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001125 · Cited by 60
“Although helper T cells are important orchestrators of many immune responses in both health and disease, their functions are commonly shaped by interactions with other immune cell types such as myeloid cells and B cells.(12) Indeed, abnormal profiles and functional responses of such non–T cells are increasingly implic…”
BackgroundCurrent Progress of CAR-NK Therapy in Cancer Treatment
Pang, Z., Wang, Z., Li, F., Feng, C., & Mu, X. N. (2022) · Cancers · doi:10.3390/cancers14174318 · Cited by 60
“To be more specific, they are αβ T cell receptor (TCR)-encoding CD8+ T cells [1].”
BackgroundEnhancer–silencer transitions in the human genomePreprint
Huang, D., & Ovcharenko, I. (2022) · Genome Research · doi:10.1101/gr.275992.121 · Cited by 57
“During embryonic development, the differentiation of T cells is a stepwise process from ESCs to mesodermal cells, HPCs, common lymphoid progenitors, and finally T cells (Kumar et al. 2018).”
BackgroundThe “root” causes behind the anti-inflammatory actions of ginger compounds in immune cells
Pázmándi, K., Szöllősi, A. G., & Fekete, T. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1400956 · Cited by 56
Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells
Wang, P., & Lu, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.877634 · Cited by 57
Borghans, J. A. M., Tesselaar, K., & de Boer, R. J. (2018) · Immunological Reviews · doi:10.1111/imr.12693 · Cited by 53
Aging and Options to Halt Declining Immunity to Virus Infections
Palacios-Pedrero, M. Á., Osterhaus, A. D. M. E., Becker, T., Elbahesh, H., Rimmelzwaan, G. F., & Saletti, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.681449 · Cited by 55
Alanio, C., Verma, A., Mathew, D., Gouma, S., Liang, G., Dunn, T. G., Oldridge, D. A., Weaver, J., Kuri-Cervantes, L., Pampena, M. B., et al. (2022) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiac020 · Cited by 52
“These effectorlike lymphocyte populations are involved in long-term control of active CMV replication [14].”
The Role of Long Non-Coding RNAs in the Tumor Immune Microenvironment
Guo, Y., Xie, Y., & Luo, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.851004 · Cited by 56
The effect of metformin on senescence of T lymphocytes
Yang, J. H., Liu, H.-C., Zhang, J., Zou, J., Zhang, X., Chen, W., Gu, Y., & Hong, H. Y. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00394-0 · Cited by 54
“As the thymus gradually shrinks with age, the number of naïve T cells decrease while memory T cells increase [19].”
BackgroundAnti-viral protective capacity of tissue resident memory T cells
Paik, D. H., & Färber, D. L. (2020) · Current Opinion in Virology · doi:10.1016/j.coviro.2020.09.006 · Cited by 53
T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome
Ríos-Ríos, W. D. J., Sosa-Luis, S. A., & Aguilar, H. T. (2020) · Biomolecules · doi:10.3390/biom10111539 · Cited by 54
“also called Cytotoxic T Lymphocytes (CTL) [4].”
The persistent inflammation in COPD: is autoimmunity the core mechanism?
Dong, L., Liu, Z., Chen, K.-J., Li, Z., Zhou, J.-S., Shen, H., & Chen, Z. (2024) · European Respiratory Review · doi:10.1183/16000617.0137-2023 · Cited by 61
“They originate from the bone marrow, with B cells maturing in the bone marrow while T cells mature in the thymus [19, 125, 126].”
BackgroundmiR-181a-regulated pathways in T-cell differentiation and aging
Kim, C., Ye, Z., Weyand, C. M., & Goronzy, J. J. (2021) · Immunity & Ageing · doi:10.1186/s12979-021-00240-1 · Cited by 55
“Tissue-resident memory T cells play an important role in protecting hosts from reinfections at local sites [60].”
BackgroundUsing the T Cell Receptor as a Biomarker in Type 1 Diabetes
Nakayama, M., & Michels, A. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.777788 · Cited by 52
Polysialic Acid in the Immune System
Villanueva-Cabello, T. M., Gutiérrez-Valenzuela, L. D., Salinas-Marín, R., López-Guerrero, D. V., & Martínez-Duncker, I. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.823637 · Cited by 50
Emerging Epigenetic‐Based Nanotechnology for Cancer Therapy: Modulating the Tumor Microenvironment
Zhang, J., Huang, L., Ge, G., & Hu, K. (2023) · Advanced Science · doi:10.1002/advs.202206169 · Cited by 52
Effects of Immune Cells and Cytokines on Different Cells in OA
Luo, P., Yuan, Q., Wan, X., Yang, M., & Xu, P. (2023) · Journal of Inflammation Research · doi:10.2147/jir.s413578 · Cited by 51
“Studies have shown that there are changes in surface receptors of T lymphocytes, and the main factor affecting their functions is their differentiation status.(41) T helper (Th) cells can interact with other immune cells (such as B lymphocytes) based on cytokines and participate in immune regulation.”
BackgroundAn Overview of Nanoparticle-Based Delivery Platforms for mRNA Vaccines for Treating Cancer
Yang, L., Chen, X., Wang, K., Li, L., & Zhang, H. (2024) · Vaccines · doi:10.3390/vaccines12070727 · Cited by 55
“As a key component of the human immune system, T cells are the focus of drug delivery in many medical applications [54].”
BackgroundYang, J., Zhang, N., Luo, T., Yang, M., Shen, W., Tan, Z., Xia, Y., Zhang, L., Zhou, X., Lei, Q., et al. (2024) · iMeta · doi:10.1002/imt2.231 · Cited by 58
“The remarkable diversity observed among T cells is mirrored by the multitude of unique states in which they exist [4].”
BackgroundT cell receptor signaling in the differentiation and plasticity of CD4+ T cells
Meitei, H. T., & Lal, G. (2022) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2022.08.001 · Cited by 58
A high‐dimensional cytometry atlas of peripheral blood over the human life span
Jalali, S., Harpur, C. M., Piers, A. T., Auladell, M. A., Perriman, L., Li, S., An, K., Anderson, J., Berzins, S. P., Licciardi, P. V., et al. (2022) · Immunology and Cell Biology · doi:10.1111/imcb.12594 · Cited by 47
Siggins, R. W., McTernan, P. M., Simon, L., Souza‐Smith, F. M., & Molina, P. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108650 · Cited by 56
Treg cell: Critical role of regulatory T-cells in depression
Gao, X. W., Tang, Y., Kong, L., Fan, Y., Wang, C., & Wang, R. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106893 · Cited by 51
Immunometabolism: A new target for improving cancer immunotherapy
Guo, C., Chen, S., Liu, W., Ma, Y., Li, J., Fisher, P. B., Fang, X., & Wang, X. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2019.03.004 · Cited by 56
Read, K. A., Jones, D. M., Freud, A. G., & Oestreich, K. J. (2020) · Immunological Reviews · doi:10.1111/imr.12936 · Cited by 52
RISING STARS: androgens and immune cell function
Ainslie, R. J., Simitsidellis, I., Kirkwood, P. M., & Gibson, D. A. (2024) · Journal of Endocrinology · doi:10.1530/joe-23-0398 · Cited by 48
“Naive T cells have yet to encounter their corresponding antigen and therefore are inactive (Kumar et al. 2018), but differentiate into an effector T cell following activation.”
BackgroundThe role of the CD8+ T cell compartment in ageing and neurodegenerative disorders
Terrabuio, E., Zenaro, E., & Constantin, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1233870 · Cited by 51
Immunomodulation and immunopharmacology in heart failure
Markousis‐Mavrogenis, G., Baumhove, L., Al‐Mubarak, A. A., Aboumsallem, J. P., Bömer, N., Voors, A. A., & van der Meer, P. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00919-6 · Cited by 51
“Immature CD4 + and CD8 + T cells express T cell receptors with random specificities and are positively or negatively selected to eliminate autoreactive T cells or T cells that do not bind to MHC molecules 21,22 .”
Omidvari, N., Jones, T., Price, P., Ferre, A. L., Lu, J. W. T., Abdelhafez, Y. G., Sen, F., Cohen, S. H., Schmiedehausen, K., Badawi, R. D., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh7968 · Cited by 48
“However, most of the immune cells involved in the adaptive immune response and immunological memory reside and function in tissue, particularly in lymphoid organs such as the bone marrow, spleen, tonsils, and lymph nodes ( 1 , 2 ).”
Steering the course of CAR T cell therapy with lipid nanoparticles
Khawar, M. B., Afzal, A., Si, Y., & Sun, H. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02630-1 · Cited by 54
“Mean-while, there are certain limitations of current mRNA delivery systems to primary T lymphocytes [103].”
BackgroundHirahara, K., Kokubo, K., Aoki, A., Kiuchi, M., & Nakayama, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.616309 · Cited by 49
New Insights into Epigenetic Regulation of T Cell Differentiation
Dutta, A., Venkataganesh, H., & Love, P. E. (2021) · Cells · doi:10.3390/cells10123459 · Cited by 52
“Immature SP thymocytes undergo further differentiation to generate either MHC Class II restricted CD4 SP helper or MHC Class I restricted CD8 SP cytotoxic lineage cells [3,4].”
BackgroundAngiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth
Menzel, L., Höpken, U. E., & Rehm, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.591741 · Cited by 50
CD8+ T cells in brain injury and neurodegeneration
Zhang, Z., Duan, Z., & Cui, Y. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1281763 · Cited by 51
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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