Abstract
The intestinal immunity and tolerance are orchestrated by both the innate and the adaptive immune system. Intestinal professional antigen presenting cells (pAPCs) recognize and respond to the gut microbiota through multiple pattern-recognition receptors, including TLRs and NLRs. How gut pAPCs maintain mucosal homeostasis remains incompletely understood. Heat shock protein gp96, also known as grp94, is an essential immune chaperone for TLRs. However, the role of gp96 in regulating CD11c+ APCs in the gut immunity and tolerance is unknown. By a genetic strategy, we report here that selective deletion of gp96 from CD11c+ cells in mice results in alteration of dendritic cell and T cell subsets in the gut as well as loss of antigen-specific regulatory T cell induction in the mesenteric lymph nodes. Strikingly, these conditional gp96-null mice developed spontaneous colitis, had increased levels of systemic and fecal IgA, and were highly susceptible to chemical-induced colitis. Our findings for the first time demonstrate that gp96 is essential for CD11c+ cells to induce regulatory T cells and maintain gut homeostasis, illustrating the importance of protein immune chaperone in safeguarding against immune pathology.
Highlights
Professional antigen presenting cells play a critical role in regulating both innate and adaptive immune responses[1]
We found that the expression levels of CD80, CD86, and ICOSL are comparable between wild type (WT) and KO dendritic cells (DCs) from spleen and mesenteric lymph node, except CD80 expression is decreased in KO splenic DCs (Fig. 2a–c). gp[96] is an essential chaperone for multiple integrins[36,37,38, 48]
We found that the migration ability of DCs from KO mice was reduced in response to the CCL21 (Fig. 2d)
Summary
Professional antigen presenting cells (pAPCs) play a critical role in regulating both innate and adaptive immune responses[1]. PAPCs including dendritic cells (DCs) and macrophages are strategically positioned to protect the gut while maintaining mucosal tolerance to food, self-antigens and microbiota. Dysregulation of interactions between the gut microbiota and the mucosal immune system causes development of chronic intestinal inflammation, which is mediated by DCs through their unique role in priming T-cell responses[31]. Our recent study demonstrated that macrophage-specific gp96-knockout mice are more resistant to DSS-induced colitis[43] These macrophage-specific gp96-knockout mice have significantly less inflammations in the colon and lower percentages of Th17 and Th1 cells in colonic lamina propria (cLP) compared with their wild type (WT) littermates[43], suggesting a critical role of gp[96] and its clientele (such as TLRs) in myeloid cells in exacerbating intestinal inflammation. Our study for the first time demonstrates the fundamental roles of gp[96] and its client network in CD11c+ cell biology and gut tolerance
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