A microbiome-reactive TMIGD2^hi Th17 subset is spatially enriched at the intestinal epithelium and expanded in...

Subsets of intestinal CD4⁺ T cells directly recognize commensal bacteria and coordinate tolerance versus protective immunity. Our limited understanding of CD4⁺ T cell specificities and corresponding functional phenotypes has created a barrier to deciphering the mechanisms of mucosal homeostasis and inflammation mediated by the adaptive immune system. To address this, we leveraged an immunodominant Bacteroidetes epitope in SusC to perform single-cell profiling of the SusC-specific and total CD4⁺ T cell landscapes in intestinal tissues of patients with inflammatory bowel disease (IBD). By analyzing phenotypes and T cell receptor specificities in parallel, we uncovered phenotypic diversification of T helper 17 (Th17) cells in IBD and identified an epithelial-localized, SusC-reactive Th17 subset that is BACH2^lo, GZMA^hi, and expresses the costimulatory receptor TMIGD2. Together, our results highlight the utility of tracking commensal-specific T cell responses to define specialized subsets of Th17 cells associated with loss of tolerance to the microbiome.