Tissue-specific features of the T cell repertoire following 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 (5-18 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, as well as
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 spleen 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 following lymphocyte-directed
therapy. These findings also underscore the importance of studying T cells
in tissues rather than blood for tissue-based pathologies and suggest the
tissue-specific nature of both the endogenous and post-transplant T cell
landscape.