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

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