MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

Abstract

Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.

Early life imprinting of intestinal immune tolerance and tissue homeostasis

“…Beyond antigen presentation by ‘professional’ APCs, intestinal epithelial cells (IECs) express MHCII and this expression can be tuned by microbial and dietary cues 23–26 . While antigen presentation by IECs modulates microbiota‐specific CD4 T cells as well as IELs, 25,27,28 with enhanced microbiota‐specific Th17 cells evident in the lamina propria of mice deficient in MHCII on IECs, it does not appear to directly contribute to pTreg differentiation which is thought to occur within gut draining lymph nodes where naïve T cells circulate.…”

Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn’s disease

“…These data confirm that yeast-responsive T H 1 cells of patients with CD who are ASCA + have cytotoxic effector functions that result in potent killing ability of IECs in vitro. IECs have been reported to function as nonconventional antigen-presenting cells (APCs), presenting antigens for intestinal microorganisms 36 . It is therefore tempting to speculate that yeast-reactive T H 1-CTLs might promote killing of IECs in vivo and thus could be involved in intestinal barrier deterioration in patients with CD, which needs further investigation.…”