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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]

Microbial diversity is associated with improved outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanism underlying this observation is unclear. In a cohort of 174 patients who underwent allo-HCT, we demonstrate that a diverse intestinal microbiome early after allo-HCT is associated with an increased number of innate-like mucosal-associated invariant T (MAIT) cells, which are in turn associated with improved overall survival and less acute graft-versus-host disease (aGVHD). Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vδ2 cells, the major circulating subpopulation of γδ T cells, closely correlated with the frequency of MAIT cells and was associated with less aGVHD. Analysis of these populations using both single-cell transcriptomics and flow cytometry suggested a shift toward activated phenotypes and a gain of cytotoxic and effector functions after transplantation. A diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vδ2 cells appeared to be necessary for the maintenance of these populations after allo-HCT. These data suggest an immunological link between intestinal microbial diversity, microbe-derived ligands, and maintenance of unconventional T cells. Unconventional transplant support: Numerous studies have suggested that a diverse intestinal microbiome is linked to better outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT). Andrlová et al. look to understand how unconventional T cell subsets facilitate this outcome in a cohort of 174 patients with allo-HCT. They observed that a diverse intestinal microbiome at early times after allo-HCT is associated with higher numbers of innate-like mucosal-associated invariant T (MAIT) cells, and this correlated with a higher prevalence of the Vδ2 subpopulation of γδ T cells and a reduced incidence of acute graft-versus-host disease (aGVHD). Further analysis indicated that a diverse intestinal microbiome could produce ligands that promote maintenance of activated and functional MAIT and Vδ2 cells following allo-HCT. These findings provide evidence of the immunological link between a diverse microbiome and maintenance of unconventional T cell subsets. [ABSTRACT FROM AUTHOR]

The article looks at a study regarding the tracking donor-reactive T cells and evidence as clonal deletion in tolerant kidney transplant patients. It mentions high-throughput sequencing of the T cell receptor B chain CDR3 region and induced in humans via combined kidney and bone marrow transplantation (CKBMT). It also mentions T cell responses to allogeneic major histocompatibility complex antigens present a formidable barrier to organ transplantation.

A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive "bystander" cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2D Hi CD8+ alpha beta T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady state tissue-resident phenotype, but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.