Tissue determinants of the human T cell receptor repertoire.

Sureshchandra, S.; Henderson, J.; Levendosky, E.; Bhattacharyya, S.; Kastenschmidt, J. M.; Sorn, A. M.; Mitul, M. T.; Benchorin, A.; Batucal, K.; Daugherty, A.; Murphy, S. J.; Thakur, C.; Trask, D.; Ahuja, G.; Moisan, A.; Tiffeau-Mayer, A.; Saligrama, N.; Wagar, L. E.

doi:10.1101/2024.08.17.608295

bioRxiv · 10.1101/2024.08.17.608295

Tissue determinants of the human T cell receptor repertoire.

Sureshchandra, S.·Henderson, J.·Levendosky, E.·Bhattacharyya, S.·Kastenschmidt, J. M.·Sorn, A. M.·Mitul, M. T.·Benchorin, A.·Batucal, K.·Daugherty, A.·Murphy, S. J.·Thakur, C.·Trask, D.·Ahuja, G.·Moisan, A.·Tiffeau-Mayer, A.·Saligrama, N.·Wagar, L. E.

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Abstract

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed from peripheral blood. We single-cell sequenced 5.7 million T cells from ten donors autologous blood and tonsils and sought to answer key questions about T cell receptor biology previously unanswerable by smaller-scale experiments. We identified distinct clonal expansions and distributions in blood compared to tonsils, with surprisingly low (1-7%) clonal sharing. These few shared clones exhibited divergent phenotypes across bodily sites. Analysis of antigen-specific CD8 T cells revealed location as a main determinant of frequency, phenotype, and immunodominance. Finally, diversity estimates from the tissue recalibrates current repertoire diversity estimates, and we provide a refined estimate of whole-body repertoire. Given the tissue-restricted nature of T cell phenotypes, functions, differentiation, and clonality revealed by this dataset, we conclude that tissue analyses are crucial for accurate repertoire analysis and monitoring changes after perturbing therapies.

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Sureshchandra, S., Henderson, J., Levendosky, E., Bhattacharyya, S., Kastenschmidt, J. M., Sorn, A. M., Mitul, M. T., Benchorin, A., Batucal, K., Daugherty, A., Murphy, S. J., Thakur, C., Trask, D., Ahuja, G., Moisan, A., Tiffeau-Mayer, A., Saligrama, N., Wagar, L. E.. 2024-08-19. Tissue determinants of the human T cell receptor repertoire.. https://doi.org/10.1101/2024.08.17.608295

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