Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity. J Clin Invest 2023 Feb 15;133(4)
Date
01/06/2023Pubmed ID
36602872Pubmed Central ID
PMC9927950DOI
10.1172/JCI162190Scopus ID
2-s2.0-85148114388 (requires institutional sign-in at Scopus site) 48 CitationsAbstract
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 found that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibited 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, epithelium-intrinsic ablation of HDAC3 decreased commensal-specific Tregs, increased commensal-specific Th17 cells, and promoted T cell-driven colitis. Mechanistically, HDAC3 was essential for NF-κB-dependent regulation of epithelial MHC class II (MHCII). Epithelium-intrinsic MHCII dampened local accumulation of commensal-specific Th17 cells in adult mice and protected against microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII expression 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 directing the dynamic balance of tissue-intrinsic CD4+ T cell subsets that recognize commensal microbes and control inflammation.
Author List
Eshleman EM, Shao TY, Woo V, Rice T, Engleman L, Didriksen BJ, Whitt J, Haslam DB, Way SS, Alenghat TAuthor
Emily M. Eshleman PhD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsHistone Deacetylases
Immunity, Innate
Inflammation
Intestines
Mice
Microbiota
