MAIT cells exacerbate colonic inflammation in a genetically diverse murine model of spontaneous colitis

IL-17-producing lymphocytes are involved in both tissue repair and the propagation of inflammation, with their effects highly context-dependent. Mucosal-Associated-Invariant-T-cells (MAIT), a subset of innate-like T cells with features of both Th1 and Th17 lineages, are increasingly recognized for their roles in mucosal immunity. Here, we identified the Collaborative-Cross CC011/Unc strain, which spontaneously develops chronic colitis, as being enriched for MAIT cells. This expansion coincides with an age-related loss of intestinal barrier permeability and colonic inflammation. Microbiota from CC011 mice activated MAIT cells in an MR1-dependent manner and selectively promoted the accumulation of MAIT17 cells in peripheral tissues. Single-cell transcriptomic analyses revealed colon MAIT cells from colitic CC011 mice expressed a pathogenic Th17-like signature, characterized by IL-1 and IL-23 signaling, IL-17A and IFNγ co-expression, and upregulation of IL-23R, features that correlated with inflammatory Ly6Chi monocyte abundance. Genetic deletion of Traj33, essential for MAIT development, significantly reduced colonic inflammation in this model. These findings demonstrate that MAIT cells integrate microbial and cytokine cues to adopt a pathogenic effector phenotype that exacerbates chronic intestinal inflammation.