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

Autor: Miron M; Department of Microbiology and Immunology, Columbia University, New York, NY, USA.; Columbia Center for Translational Immunology, Columbia University, New York, NY, USA., Meng W; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Rosenfeld AM; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Dvorkin S; Department of Mathematics, Bar Ilan University, Ramat Gan, Israel., Poon MML; Department of Microbiology and Immunology, Columbia University, New York, NY, USA., Lam N; Department of Microbiology and Immunology, Columbia University, New York, NY, USA.; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA., Kumar BV; Columbia Center for Translational Immunology, Columbia University, New York, NY, USA., Louzoun Y; Department of Mathematics, Bar Ilan University, Ramat Gan, Israel., Luning Prak ET; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. luning@pennmedicine.upenn.edu., Farber DL; Department of Microbiology and Immunology, Columbia University, New York, NY, USA. df2396@cumc.columbia.edu.; Department of Surgery, Columbia University, New York, NY, USA. df2396@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2021 Jun 14; Vol. 13 (1), pp. 100. Date of Electronic Publication: 2021 Jun 14.
DOI: 10.1186/s13073-021-00918-7
Abstrakt: 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.
Databáze: MEDLINE
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