Compartmentalized antigen presentation and inflammasome activation between epithelial cells and macrophages orchestrates gut immunity

Abstract All nucleated cells express MHCI and IFN-gR. It is suggested that structural to prevent NK-cell mediated cytotoxicity allow deletion by CD8 +T upon intracellular perturbations, but a cell-specific function of antigen presentation via has not been explored. We show here sensing IFN-g, colonic epithelial productively present pathogen self-derived antigens the cognate intra-epithelial T cells, which are critically located at barrier. Antigen confers ATPase expression in limits accumulation extracellular ATP consequent activation NLRP3 inflammasome tissue macrophages. In contrast, macrophages alongside inflammasome-associated IL-1a IL-1b production promotes pathogenic transformation CD4 into GM-CSF-producing vivo, underlies colitis colorectal cancer. Supporting relevance these findings humans, we IBD-associated IFN-gR SNP leads defective IFN-g signaling. Furthermore, decreased or increased GM-CSF associated with IBD resistant standard therapies, reduced survival Taken together, our study unraveled critical checkpoint requiring control development cell responses vivo. Supported US National Institutes Health (DK067180) B.J, University Chicago's Center for Interdisciplinary Study Inflammatory Intestinal Disorders (C-IID) Pilot & Feasibility Award (NIDDK P30 DK042086) A.M. D.S, Crohn’s Colitis Foundation Career Development #964209 G.I. Research Associates Board D.S.