Maintenance of the human memory T cell repertoire by subset and tissue site

Michelle Miron, Wenzhao Meng, Aaron M. Rosenfeld, Shirit Dvorkin, Maya Meimei Li Poon, Nora Lam, Brahma V. Kumar, Yoram Louzoun, Eline T. Luning Prak, Donna L. Farber

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background: Immune-mediated protection is mediated by T cells expressing pathogen-specific T cell antigen receptors (TCR) that are maintained at diverse sites of infection as tissue-resident memory T cells (TRM) or that disseminate as circulating effector-memory (TEM), central memory (TCM), or terminal effector (TEMRA) subsets in blood and tissues. The relationship between circulating and tissue resident T cell subsets in humans remains elusive, and is important for promoting site-specific protective immunity. Methods: We analyzed the TCR repertoire of the major memory CD4+ and CD8+T cell subsets (TEM, TCM, TEMRA, and TRM) isolated from blood and/or lymphoid organs (spleen, lymph nodes, bone marrow) and lungs of nine organ donors, and blood of three living individuals spanning five decades of life. High-throughput sequencing of the variable (V) portion of individual TCR genes for each subset, tissue, and individual were analyzed for clonal diversity, expansion and overlap between lineage, T cell subsets, and anatomic sites. TCR repertoires were further analyzed for TRBV gene usage and CDR3 edit distance. Results: Across blood, lymphoid organs, and lungs, human memory, and effector CD8+T cells exhibit greater clonal expansion and distinct TRBV usage compared to CD4+T cell subsets. Extensive sharing of clones between tissues was observed for CD8+T cells; large clones specific to TEMRA cells were present in all sites, while TEM cells contained clones shared between sites and with TRM. For CD4+T cells, TEM clones exhibited the most sharing between sites, followed by TRM, while TCM clones were diverse with minimal sharing between sites and subsets. Within sites, TRM clones exhibited tissue-specific expansions, and maintained clonal diversity with age, compared to age-associated clonal expansions in circulating memory subsets. Edit distance analysis revealed tissue-specific biases in clonal similarity. Conclusions: Our results show that the human memory T cell repertoire comprises clones which persist across sites and subsets, along with clones that are more restricted to certain subsets and/or tissue sites. We also provide evidence that the tissue plays a key role in maintaining memory T cells over age, bolstering the rationale for site-specific targeting of memory reservoirs in vaccines and immunotherapies.

Original languageEnglish
Article number100
JournalGenome Medicine
Volume13
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

This work was supported by NIH AI106697 and AI128949 awarded to D.L.F. and AI106697 awarded to E.L.P. M.M. was supported by NIH T32AI06711. B.K. was supported by TL1 TR001875. Research reported here was performed in the CCTI Flow Cytometry Core, supported by award S10RR027050 & S10OD020056 and the Perelman School of Medicine Human Immunology Core, supported by P30-CA016520 and P30-AI0450080.

FundersFunder number
National Institutes of HealthAI128949, AI106697, TL1 TR001875, T32AI06711
National Cancer InstituteP30CA016520

    Keywords

    • Immunity
    • Immunogenomics
    • Immunology
    • T cell

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