Thymic microbiota-specific T cells role in intestinal inflammation

Abstract Inflammatory bowel disease (IBD) patients, including Crohn’s disease and ulcerative colitis, exhibit dysregulated immune responses. Although IBD etiology remains uncertain, microbiota-reactive T cells are thought to play a role in pathogenesis. It has been shown that gut microbiota and their metabolites play a role in modulating mucosal immune responses and thus, have the potential to influence the development of IBD. Although host-microbe interactions are required to balance effector and regulatory T cells responses, it remains unknown how microbiota-specific T cells are generated. Here we studied how microbiota-specific T cells develop and how they can drive intestinal inflammation. Colonization of mice at weaning induced the expansion of naive microbiota-specific T cells in the thymus before peripheral distribution. Transfer of naive thymic microbiota-specific T cells into immunodeficient mice induced intestinal inflammation by differentiating into Th1 or Th17 cells. We identified that CX3CR1+ dendritic cells (CX3+DCs) were required for this process, as depleting these cells decreased the expansion of thymic microbiota-specific T cells. Transfer of thymic T cells from mice lacking CX3+ DCs induced less colitis in immunodeficient mice compared to wildtype donors. Moreover, inhibiting CX3+ DCs antigen-presentation suppressed induction of microbiota-specific T cells and transfer of these cells promoted less intestinal inflammation. Together, our data suggests CX3+ DCs drive T cell selection of microbiota-specific T cells in the thymus, which can differentiate into intestinal effector T cells mediating pathology in immunodeficient hosts.