Maintenance of the human memory T cell repertoire by subset and tissue site
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),...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-021-00918-7 |
| _version_ | 1818407443382665216 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Michelle Miron |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T09:27:55Z |
| format | Article |
| id | doaj.art-c9735e3dd8794a808679dc6e6b7b0c8f |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-14T09:27:55Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-c9735e3dd8794a808679dc6e6b7b0c8f2022-12-21T23:08:09ZengBMCGenome Medicine1756-994X2021-06-0113111410.1186/s13073-021-00918-7Maintenance of the human memory T cell repertoire by subset and tissue siteMichelle Miron0Wenzhao Meng1Aaron M. Rosenfeld2Shirit Dvorkin3Maya Meimei Li Poon4Nora Lam5Brahma V. Kumar6Yoram Louzoun7Eline T. Luning Prak8Donna L. Farber9Department of Microbiology and Immunology, Columbia UniversityDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Mathematics, Bar Ilan UniversityDepartment of Microbiology and Immunology, Columbia UniversityDepartment of Microbiology and Immunology, Columbia UniversityColumbia Center for Translational Immunology, Columbia UniversityDepartment of Mathematics, Bar Ilan UniversityDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Microbiology and Immunology, Columbia UniversityAbstract 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.https://doi.org/10.1186/s13073-021-00918-7ImmunogenomicsImmunologyT cellImmunity |
| spellingShingle | 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 Maintenance of the human memory T cell repertoire by subset and tissue site Genome Medicine Immunogenomics Immunology T cell Immunity |
| title | Maintenance of the human memory T cell repertoire by subset and tissue site |
| title_full | Maintenance of the human memory T cell repertoire by subset and tissue site |
| title_fullStr | Maintenance of the human memory T cell repertoire by subset and tissue site |
| title_full_unstemmed | Maintenance of the human memory T cell repertoire by subset and tissue site |
| title_short | Maintenance of the human memory T cell repertoire by subset and tissue site |
| title_sort | maintenance of the human memory t cell repertoire by subset and tissue site |
| topic | Immunogenomics Immunology T cell Immunity |
| url | https://doi.org/10.1186/s13073-021-00918-7 |
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