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

Abstract

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.

Single-cell genomics-based immune and disease monitoring in blood malignancies

“…The latter question has recently been addressed by DeWolf et al in a systematic study of TCR repertoires across multiple different tissue sites. 71 The authors identified anatomically defined TCR repertoires and motifs that only partially overlapped with circulating TCR repertoires, underscoring the importance of the study of tissue-resident memory T cells. Besides providing a deeper understanding of T cells, scRNA-seq studies of tissue biopsies should also investigate the role of other cell types in the pathogenesis of GvHD, such as B cells, for which Poe et al have provided a baseline by defining their transcriptional profiles in peripheral blood and bone marrow.…”

Separation of GVL from GVHD -location, location, location

“…However, late-phase GVHD is maintained within affected tissues locally by tissue-resident TCF1 + pTex-like cells without migrating between target organs ( 83 ). In patients with multiple sites of GVHD, the dominant T cell receptor repertoires are not consistently observed across tissues within the same patient, raising the possibility that GVHD arose in each local tissue independently ( 84 ). Furthermore, patient-derived resident memory T cells persist for many years after HCT in association with the development of skin GVHD ( 85 ).…”