Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells
Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells
Abstract Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we find that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibit increased accumulation of commensal-specific CD4+ T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity. Consistent with this, microbiota-specific CD4+ T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelial-intrinsic ablation of HDAC3 promoted T cell driven-colitis and primed development of pathogenic commensal-specific Th17 cells. Mechanistically, HDAC3 was essential for MHC class II (MHCII) expression by the intestinal epithelium, and epithelial-intrinsic MHCII actively limited commensal-specific Th17 cells and prevented microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in controlling development of tissue-intrinsic T cells that recognize commensal microbes and drive pathologic inflammation.
Whitt Jordan、Shao Tzu-Yu、Way Sing Sing、Eshleman Emily M.、Engleman Laura、Rice Taylor、Alenghat Theresa、Woo Vivienne
Division of Immunobiology, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Infectious Disease, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Immunology Graduate Program, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Infectious Disease, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Immunobiology, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Immunobiology, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Immunobiology, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Immunobiology, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of MedicineDivision of Immunobiology, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine||Center for Inflammation and Tolerance, Cincinnati Children?ˉs Hospital Medical Center and the University of Cincinnati College of Medicine
基础医学微生物学
Whitt Jordan,Shao Tzu-Yu,Way Sing Sing,Eshleman Emily M.,Engleman Laura,Rice Taylor,Alenghat Theresa,Woo Vivienne.Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.01.01.473735.点此复制
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