Aryl Hydrocarbon Receptor Signaling Cell Intrinsically Inhibits Intestinal Group 2 Innate Lymphoid Cell Function

Abstract

<p id="P3">Innate lymphoid cells (ILCs) are important for mucosal immunity. The intestine harbors all ILC subsets, but how these cells are balanced to achieve immune homeostasis and mount appropriate responses during infection remains elusive. Here, we show that aryl hydrocarbon receptor (Ahr) expression in the gut regulated ILC balance. Among ILCs, Ahr was most highly expressed by gut ILC2s, and controlled chromatin accessibility at the <i>Ahr</i> gene locus via positive feedback. Ahr signaling suppressed Gfi1 transcription factor-mediated expression of the interleukin 33 receptor ST2 in ILC2s and expression of ILC2 effector molecules IL-5, IL-13 and amphiregulin in a cell-intrinsic manner. Ablation of Ahr enhanced anti-helminth immunity in the gut, while genetic or pharmacological activation of Ahr suppressed ILC2 function but enhanced ILC3 maintenance to protect the host from <i>Citrobacter rodentium</i> infection. Thus, the host regulates the gut ILC2-ILC3 balance by engaging the Ahr pathway to mount appropriate immunity against various pathogens. </p><p id="P4">The aryl hydrocarbon receptor (Ahr) promotes ILC3 maintenance and function. Li et al. report that Ahr restricts intestinal ILC2 function in a cell-intrinsic manner, suggesting a central role for gut adaptation of Ahr expression in regulating the ILC2-ILC3 balance. </p><p id="P5"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/c2e952a3-4681-48b5-9c83-43329104ee49/PubMedCentral/image/nihms-1508207-f0008.jpg"/> </div> </p>