Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites

Nora Lam¹, J Carlos Angel², Bruce A Buchholz³, YoonSeung Lee⁴, Stuart P Weisberg⁵, Brea H Brown⁴, Julia Davis-Porada⁶, Daniel P Caron⁴, Isaac J Jensen⁴, Peter A Szabo⁴, Basak B Ural⁴, Steven B Wells⁷, Masaru Kubota⁸, Rei Matsumoto⁸, Maigan Brusko⁹, Todd M Brusko⁹, Chao Lu¹⁰, Andrew J Yates⁵, Donna L Farber¹¹

Affiliations

¹ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
² Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA; New York Genome Center, New York, NY 10013, USA.
³ Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
⁴ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁵ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁶ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Medical Scientist Training Program, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁷ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁸ Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁹ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
¹⁰ Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹¹ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: df2396@cumc.columbia.edu.

PMID: 40738109
PMCID: PMC12321214 (available on 2026-07-29)
DOI: 10.1016/j.immuni.2025.07.001

Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites

Nora Lam et al. Immunity. 2025.

. 2025 Sep 9;58(9):2271-2288.e6.

doi: 10.1016/j.immuni.2025.07.001. Epub 2025 Jul 29.

Authors

Affiliations

¹ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
² Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA; New York Genome Center, New York, NY 10013, USA.
³ Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
⁴ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁵ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁶ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Medical Scientist Training Program, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁷ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁸ Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁹ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
¹⁰ Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹¹ Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: df2396@cumc.columbia.edu.

PMID: 40738109
PMCID: PMC12321214 (available on 2026-07-29)
DOI: 10.1016/j.immuni.2025.07.001

Abstract

Memory T cells are maintained in tissues as circulating effector-memory (T_EM) and tissue-resident (T_RM) populations for protective immunity, though the role of site and subset in memory persistence remains undefined. Here, we investigated age-associated dynamics of human T cells in lymphoid organs, mucosal sites, and blood over 10 decades of life using retrospective radiocarbon (¹⁴C) birth dating, along with cellular, transcriptome, and epigenetic profiling. Memory T cells across peripheral sites exhibited continuous turnover with mean lifespans of 1-2 years, while the spleen contained longer-lived T cells. Over age, T_EM cells expressed senescent markers and a GZMK transcriptional signature, while T_RM cells maintained site-specific resident phenotypes without exhibiting features of senescence. Both T_EM and T_RM cells showed age-associated DNA hypomethylation, though T_RM cells exhibited more epigenetically regulated genes. Together, our findings reveal asynchronous aging of human memory T cells by subset and site, as well as persistence of T_RM cells without immunosenescence.

Keywords: T cells; aging; epigenetics; histology; immunosenescence; mucosal immunity; tissue-resident memory T cells.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites

Affiliations

Asynchronous aging and turnover of human circulating and tissue-resident memory T cells across sites

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical