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.

主要组织相容性复合体 II 类 (MHCII) 在整个肠道的肠上皮细胞 (IEC) 上动态表达，但其调节机制仍知之甚少。我们观察到，本地繁殖的Rag1 ^-/-小鼠中 IEC MHCII 的自发上调与血清白细胞介素 (IL)-18 相关，可通过共同饲养转移至商业繁殖的免疫缺陷小鼠，并可被 IL-12 和 IL-18 抑制封锁。激活Nlrc4导致肠道 IL-18 过量产生突变通过独立于免疫缺陷或生态失调的经典炎性体机制上调 IEC MHCII。免疫缺陷的生态失调增加了 Il-18 的转录，它与 NLRC4 炎性体活性协同作用，导致血清 IL-18 升高。这种 IL-18-MHCII 轴在其他几种肠道和全身炎症模型中得到证实。IL-18 升高可靠地先于 MHCII 上调，表明对 IEC 有间接影响，IL-18 过量产生的小鼠显示 1 型淋巴细胞的激活或扩增。干扰素伽马 (IFNg) 具有独特的能力，可以在肠样培养物中上调 IEC MHCII，并且是多个体内系统中 MHCII 上调所必需的。因此，我们通过肠道 IL-18-IFNg 轴将肠道生态失调、全身炎症和炎性体活动与 IEC MHCII 上调联系起来。