Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity
Emily M. Eshleman, … , Sing Sing Way, Theresa Alenghat
Emily M. Eshleman, … , Sing Sing Way, Theresa Alenghat
Published January 5, 2023
Citation Information: J Clin Invest. 2023;133(4):e162190. https://doi.org/10.1172/JCI162190.
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Research Article Gastroenterology Immunology

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

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 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.

Authors

Emily M. Eshleman, Tzu-Yu Shao, Vivienne Woo, Taylor Rice, Laura Engleman, Bailey J. Didriksen, Jordan Whitt, David B. Haslam, Sing Sing Way, Theresa Alenghat

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Figure 1

Epithelial HDAC3 expression limits commensal-specific CD4+ T cells in the intestine.

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Epithelial HDAC3 expression limits commensal-specific CD4+ T cells in th...
(A and B) Number of cBir1+ tetramer-specific CD4+ T cells isolated from large intestine of neonatal GF and CNV pups. (C) mRNA expression of HDAC3 in IECs isolated from large intestine of GF and CNV pups. (D and E) Frequency of total intestinal CD3+. (F and G) Frequency of total intestinal CD8a+ (F) and CD4+ (G) T cells. (H–K) Number of cBir1+ tetramer-specific CD4+ T cells (H and I) and frequency of RORγt+ (J) and FoxP3+ (K) cBir1+CD4+ T cells in large intestine of HDAC3FF and HDAC3ΔIEC mice. cBir1+ tetramer cells are gated on live, CD45+, lineage (CD11b–B220–Ly6G–, CD11c–CD8a–, CD4+. Data are representative of at least 2 experiments, 3–4 mice per group. *P < 0.05, **P < 0.01, ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple-comparison test (B) or unpaired 2-tailed Student’s t test (C–K).