Multimodal immune cell phenotyping in GI biopsies reveals microbiome-related T cell modulations in human GvHD

Acute graft-versus-host disease (aGvHD) is a significant complication after allogeneic hematopoietic stem cell transplantation (aHSCT), but major factors determining disease severity are not well defined yet. By combining multiplexed tissue imaging and single-cell RNA sequencing on gastrointestinal biopsies from aHSCT-treated individuals with fecal microbiome analysis, we link high microbiome diversity and the abundance of short-chain fatty acid-producing bacteria to the sustenance of suppressive regulatory T cells (Tregs). Furthermore, aGvHD severity strongly associates with the clonal expansion of mainly CD8 T cells, which we find distributed over anatomically distant regions of the gut, persistent over time, and inversely correlated with the presence of suppressive Tregs. Overall, our study highlights the pathophysiological importance of expanded CD8 T cell clones in the progression of aGvHD toward more severe clinical manifestations and strongly supports the further development of microbiome interventions as GvHD treatment via repopulation of the gut Treg niche to suppress inflammation. [Display omitted] •Antibiotic exposure correlates with reduced Treg abundance in the gut•Peripheral gut Treg differentiation is altered in antibiotic-exposed individuals•GvHD severity associates with clonal expansion of activated CD8 T cells•GvHD-associated clones are persistent over time and distributed within the GI tract Jarosch et al. describe a link between clonally expanded CD8 T cells and GvHD severity, as well as the potential of GvHD suppression via microbiome-dependent Tregs. These findings support the concept of microbiome interventions as a GvHD treatment option and can serve as a starting point for the development of novel therapies.