Maintenance of the human memory T cell repertoire by subset and tissue site
| Autor: | Shirit Dvorkin, Maya Meimei Li Poon, Yoram Louzoun, Nora Lam, Brahma V Kumar, Eline T. Luning Prak, Donna L. Farber, Michelle Miron, Wenzhao Meng, Aaron M. Rosenfeld |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male T cell Immunology Receptors Antigen T-Cell Spleen Biology QH426-470 Lymphocyte Activation Models Biological Clonal Evolution Immunogenomics Memory T Cells T-Lymphocyte Subsets medicine Genetics Humans Cell Lineage Immunogenetic Phenomena Molecular Biology Gene Genetics (clinical) Aged Aged 80 and over Effector Research T-cell receptor Age Factors Immunity Computational Biology Genetic Variation Middle Aged Molecular biology medicine.anatomical_structure Lymphatic system Organ Specificity Leukocytes Mononuclear Molecular Medicine Medicine Female Bone marrow Immunologic Memory CD8 |
| Zdroj: | Genome Medicine, Vol 13, Iss 1, Pp 1-14 (2021) Genome Medicine |
| DOI: | 10.7916/5ee2-td04 |
| Popis: | BackgroundImmune-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.MethodsWe 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 forTRBVgene usage and CDR3 edit distance.ResultsAcross blood, lymphoid organs, and lungs, human memory, and effector CD8+T cells exhibit greater clonal expansion and distinctTRBVusage 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.ConclusionsOur 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: | OpenAIRE |
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