Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ

Abstract

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 cohousing 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 Il18 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.

Epithelial antigen presentation controls commensal-specific intraepithelial T-cells in the gut

“…At this time point, mice start to consume solid food and this leads to profound changes in microbiota composition initiating a robust immune response (Al Nabhani et al, 2019). While it is known that MHCII expression on IECs affects the severity of various immunopathologies (Jamwal et al ., 2020; Thelemann et al, 2014) and is dependent on intestinal microbiota (Van Der Kraak et al, 2021), very little is known about the role of MHCII + IECs in regard to time-dependent microbiota responses. Specifically, it is still unclear when exactly IECs start to express MHCII, what specific signals induce it, or whether it conveys any of the time-dependent microbiota-induced stimuli.…”

“…While SFB are best known for their induction of a T H 17 response (Gaboriau-Routhiau et al ., 2009; Ivanov et al ., 2009), it was also reported that SFB can increase IFNγ production in the gut (Gaboriau-Routhiau et al ., 2009). The latter finding may be crucial since IFNγ is a well-documented modulator of MHCII expression (Koyama et al ., 2019; Thelemann et al ., 2014; Van Der Kraak et al ., 2021). Therefore, we next measured the induction of IL-17a and IFNγ cytokines in the SI-LP after SFB colonization of JAX mice.…”

“…While several recent studies described that MHCII presence in the intestinal epithelium is dependent on IFNγ (Al Nabhani et al ., 2019; Koyama et al ., 2019; Thelemann et al ., 2014; Van Der Kraak et al ., 2021), the source of this cytokine and the regulation of its production remained unclear. We have shown that under homeostatic conditions T H 1 cells are the major source of IFNγ, responsible for the induction of MHCII on IECs.…”

“…At this time point, mice start to consume solid food and this leads to profound changes in microbiota composition initiating a robust immune response (Al Nabhani et al, 2019). While it is known that MHCII expression on IECs affects the severity of various immunopathologies (Jamwal et al, 2020;Thelemann et al, 2014) and is dependent on intestinal microbiota (Van Der Kraak et al, 2021) Having determined the diversity of LP immune cells, we next analyzed changes in the relative abundance of the individual subsets throughout the period of 3-6 weeks of mice age. The most obvious phenomenon was the gradual increase in the frequency of plasma cells (Figure 1D, top-left panel), the majority of which expressed IgA antibody isotype (encoded by the Igha gene) (Figure S1A).…”

Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells

“…Previous studies have linked the requirement for the microbiota in regulating IEC-intrinsic MHCII expression (44–48). Many of these studies have focused on how immune cells can induce epithelial MHCII through IFNγ signaling (44, 71, 72). In addition, disruption to canonical pattern recognition pathways leads to loss of intestinal barrier integrity and increased inflammation (73–75), and the toll-like receptor signaling adaptors MyD88/TRAF have been shown to induce epithelial MHCII expression, particularly in the small intestine (44).…”