Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B102
Abstract ID: 4449

Presenting Author:
Emily M Eshleman , Instructor at Cincinnati Children’s Hosp. Med. Ctr., Univ. of Cincinnati Col. of Med.

Abstract:

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. In this study, we found that butyrate-producing commensal bacteria suppress tuft cell-dependent type 2 immunity in the intestine. Inhibition of tuft cells by butyrate required the microbiota-sensitive epigenetic modifying enzyme histone deacetylase 3 (HDAC3), suggesting that HDAC3 may control tuft cell-dependent immune responses. 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. Furthermore, butyrate and butyrate-producing commensal bacteria epigenetically restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in mice and human intestinal organoids was sufficient to block tuft cell differentiation. Mechanistically, microbiota-derived butyrate limited tuft cell differentiation, in part, by decreasing HDAC3 activity at the tuft cell suppressor gene, Sprouty2. Collectively, these findings 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.