Major histocompatibility complex class II (MHCII) is dynamically expressed on intestinal epithelial cells (IECs) throughout the intestine, but its regulation remains poorly understood. We observed that spontaneous upregulation of IEC MHCII in locally bred Rag1−/− mice correlated with serum Interleukin (IL)-18, was transferrable via co-housing to commercially bred immunodeficient mice and could be inhibited by both IL-12 and IL-18 blockade. Overproduction of intestinal IL-18 due to an activating Nlrc4 mutation upregulated IEC MHCII via classical inflammasome machinery independently of immunodeficiency or dysbiosis. Immunodeficient dysbiosis increased Il-18 transcription, which synergized with NLRC4 inflammasome activity to drive elevations in serum IL-18. This IL-18-MHCII axis was confirmed in several other models of intestinal and systemic inflammation. Elevated IL-18 reliably preceded MHCII upregulation, suggesting an indirect effect on IECs, and mice with IL-18 overproduction showed activation or expansion of type 1 lymphocytes. Interferon gamma (IFNg) was uniquely able to upregulate IEC MHCII in enteroid cultures and was required for MHCII upregulation in several in vivo systems. Thus, we have linked intestinal dysbiosis, systemic inflammation, and inflammasome activity to IEC MHCII upregulation via an intestinal IL-18-IFNg axis. Understanding this process may be crucial for determining the contribution of IEC MHCII to intestinal homeostasis, host defense, and tolerance.
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S.C., C.S., and V.D. were supported by NICHD R01HD098428. L.V.D.K. and A.H.P.B. were supported by autoimmunity and immunopathology T32 (5T32AI089443-11). T.H. was supported by the Kenneth Rainin Foundation and R01DK120697. We also thanks Drs. Daniel Kastner and Jae Jin Chae (NHGRI); Dario Vignali, Warren Shlomchik, and Sarah Gaffen (University of Pittsburgh); Tomoaki Hoshino (Kurume University); and Richard Flavell (Yale University) for sharing key reagents.
The authors declare no competing interests.
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Van Der Kraak, L.A., Schneider, C., Dang, V. et al. Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ. Mucosal Immunol (2021). https://doi.org/10.1038/s41385-021-00419-1