Molecular chaperone is required for gut tolerogenic dendritic cell development and function

Abstract

Abstract The intestinal mucosa is continuously inundated with foreign antigens. Therefore, immune cells need to be tightly regulated to maintain tolerance against harmless dietary antigens and microbiota while responding to pathogens. Intestinal dendritic cells (DCs) play an integral role in regulating immunity and tolerance because of their unique position at the interface of innate and adaptive immunity. Multiple populations of intestinal DCs have been reported based on the expression of CD103, CD11b, and CX3CR1. However, the mechanism by which different DC subsets regulate intestinal homeostasis is still unclear. Heat shock protein gp96 is an essential chaperone for most TLRs, integrins, and other proteins important for DC functions. However, the role of DC-intrinsic gp96 in regulating gut tolerance has not been studied. By a genetic strategy, we discovered that selective deletion of gp96 from CD11c+ cells in mice results in alteration of DC and T cell subsets in the gut as well as the loss of antigen-specific regulatory T cell (Treg) induction. Strikingly DC-specific gp96 knockout mice develop spontaneous colitis by 24 weeks of age. Furthermore, differentiation of murine bone marrow-derived DCs revealed that gp96 depletion selectively decreased cell maturation in response to FLT3L compared to CSF2. Also, gp96 depletion reduced DC migration and cross-presentation. Taken together, our results demonstrated that gp96 depletion from CD11c+ cells selectively inhibits tolerogenic DCs in the gut leading to decreased Treg cells, which indicates that DC-intrinsic gp96 plays essential roles in maintaining gut tolerance.