Deep profiling of human T cells defines compartmentalized clones and phenotypic trajectories across blood and tonsils
Suhas Sureshchandra, James Henderson, Elizabeth Levendosky, Sankalan Bhattacharyya, Jenna M. Kastenschmidt, Andrew M. Sorn, Mahina Tabassum Mitul, Timothy B. Yates, Evien Cheng, Aviv I. Benchorin, Kyle Batucal, Allyssa L. Daugherty, Samuel J. H. Murphy, Chandrani Thakur, Douglas K. Trask, Gurpreet S. Ahuja, Qiu Zhong, Annie Moisan, Andreas Tiffeau-Mayer, Naresha Saligrama, Lisa E. Wagar
Abstract
98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct T cell clones from naive or tissue-resident memory pools. Finally, we demonstrate that chronic infections influence TCR repertoire diversity differently in blood and tonsil-resident T cells. These data highlight the necessity of accounting for tissue-specific contexts to accurately measure the TCR repertoire and monitor T cell responses following perturbing therapies.