B-Cells and Dendritic Cells React to Intestinal Epithelial Stress with a Coordinated and Protective IgA Response.

X-box binding protein-1 deletion in intestinal epithelium (Xbp1^ΔIEC) induces endoplasmic reticulum (ER) stress resulting in microbiota-dependent enteritis. Compensatory mechanisms like autophagy have been shown to limit inflammation. Here, we show that plasma cell IgA production is another important compensatory mechanism dampening intestinal inflammation. IEC ER-stress increases lamina propria (LP) CCR9⁺IgA⁺CD138⁺ plasma cells and IgA levels. Xbp1^ΔIEC mice with concomitant B cell deficiency (μMT) exhibit increased enteritis compared to Xbp1^ΔIEC mice. The IgA response was T cell dependent, and not independent, as observed by normal BAFF, APRIL and TSLP levels and increased Fas⁺GL7⁺ germinal center (GC) B-cells and T follicular helper (Tfh) cells in Peyer’s patches (PP) of Xbp1^ΔIEC mice. The microbiota was indispensable for the protective IgA response because germ free mice lacked increased GC and Tfh in PP and IgA⁺ plasma cells in LP. In light of the T cell dependency, we investigated whether dendritic cell (DC) populations played a role in this IgA protective response. Interestingly, we found that Xbp1^ΔIEC mice had higher numbers of intraepithelial CD11c⁺CD11b⁺CD103⁺ DCs. Although Xbp1^ΔDC mice lacked enteritis, loss of DC in Xbp1^ΔIEC/DC reversed the protective IgA response with increased enteritis like μMT- Xbp1^ΔIEC. In conclusion, we show that microbially-induced, epithelial ER (dis)stress in a genetically at risk barrier is sensed by B cells and DC in PP resulting in a protective IgA response which is crucial to limiting enteritis. We hypothesize that epithelial ER (eu)stress under homeostatic conditions may be an important mechanism that controls small intestinal IgA responses.