Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity

All nucleated cells express major histocompatibility complex I and interferon-gamma (IFN gamma) receptor1, but an epithelial cell-specific function of IFN gamma signalling or antigen presentation by means of major histocompatibility complex I has not been explored. We show here that on sensing IFN gamma, colonic epithelial cells productively present pathogen and self-derived antigens to cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers extracellular ATPase expression in cognate intra-epithelial T cells, which limits the accumulation of extracellular adenosine triphosphate and consequent activation of the NLRP3 inflammasome in tissue macrophages. By contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated interleukin-1 alpha and interleukin-1 beta production promotes a pathogenic transformation of CD4+ T cells into granulocyte-macrophage colony-stimulating-factor (GM-CSF)-producing T cells in vivo, which promotes colitis and colorectal cancer. Taken together, our study unravels critical checkpoints requiring IFN gamma sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4+ T cell responses in vivo. IFN gamma signalling in epithelial cells promotes antigen presentation that confers intra-epithelial T cells the ability to limit extracellular ATP and consequent NLRP3 inflammasome activation, controlling pathogenic transformation of CD4+ T cells that promotes colitis and colorectal cancer in mouse models.