Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse.

T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape. Editor's summary: Numerous studies have relied on analyzing peripheral blood to understand how T cells mediate graft-versus-host disease (GVHD) but little is known about these responses at the tissue level. DeWolf et al. compared site-specific T cell receptor (TCR) repertoires across a range of tissues from prospectively collected autopsies from patients with or without GVHD and in GVHD murine models. They consistently found similar TCR repertoires in tissues from similar anatomic sites regardless of patient disease status and confirmed that TCRs in peripheral blood offered a narrow view of the TCR repertoire observed in tissues. They also detected tissue-resident T cells at disease sites in some patients with evidence for donor origin. This study provides insight into the T cell composition in tissues associated with GVHD and highlights the powerful insights gained from directly analyzing tissues. —Christiana Fogg [ABSTRACT FROM AUTHOR]