Biology subjects

Eshleman, E. M.

Publications and source records attributed to Eshleman, E. M..

3 recordsLinked to original sources

bioRxiv2023

Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

Allergy and anti-helminth immunity are driven by type 2 responses in mucosal tissues. Tuft cells are key regulators of type 2 immunity, however the factors that control these cells remain poorly understood. Here we find that butyrate-producing commensal bacteria decrease tuft cells in the intestine. Butyrate suppression of tuft cells required the epigenetic modifying enzyme histone deacetylase 3 (HDAC3), suggesting that HDAC3 may promote tuft cell-dependent immunity. Consistent with this, epithelial-intrinsic HDAC3 actively regulated tuft cell expansion in vivo and was required to induce type 2 immune responses during helminth infection. Interestingly, butyrate epigenetically restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids was sufficient to block tuft cell expansion. Collectively, these data reveal an epigenetic pathway in stem cells that directs tuft cell differentiation, and highlight a new level of regulation through which commensal bacteria calibrate intestinal immunity.

immunology↗

bioRxiv2022

Epithelial MHC class II directs microbiota-specific intestinal immune homeostasis

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.

immunology↗

bioRxiv2021

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

Interactions between the microbiota and mammalian host are essential for effective defense against pathogenic infection; however, the microbial-derived cues that mediate this beneficial relationship remain unclear. Here, we find that the intestinal epithelial cell (IEC)-associated commensal bacteria, Segmented Filamentous Bacteria (SFB), promotes early protection against the bacterial pathogen, Citrobacter rodentium, independently of CD4+ T cells. Global analyses demonstrated that SFB induced histone modifications in IECs at sites enriched for the retinoic acid receptor (RAR) motif. Interestingly, SFB-colonized mice exhibited greater expression of RAR targets during infection relative to germ-free mice, suggesting SFB may enhance defense through retinoic acid (RA) signaling. Consistent with this, supplementing germ-free mice with RA decreased pathogen levels. Further, mice with impaired RA-responsiveness in IECs displayed increased susceptibility to C. rodentium infection. RA was elevated in the intestine of mice colonized with SFB, indicating that the presence of commensal bacteria can modulate intestinal RA levels. However, this regulation by SFB was not dependent on mammalian RA production. Sequence analyses suggested that RA-generating enzymes are expressed by a subset of commensal bacteria. Remarkably, RA was produced by intestinal bacteria including SFB, and inhibiting RA signaling blocked SFB-induced protection against C. rodentium infection. These data collectively reveal RA as an unexpected microbiota-derived metabolite that primes innate intestinal defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat pathogenic infection.

microbiology↗