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

Abstract

SUMMARY 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 Ahr 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 Citrobacter rodentium infection. Thus, the host regulates the gut ILC2-ILC3 balance by engaging the Ahr pathway to mount appropriate immunity against various pathogens.

ILC2s are the predominant source of intestinal ILC-derived IL-10

“…Activated lung ILC2s were previously shown to produce IL-10 after chronic papain exposure and in response to IL-2 (Miyamoto et al, 2019; Seehus et al, 2017). To identify factors that could induce IL-10 in intestinal ILC2s, purified eGFP-negative ILC2s from the small intestine lamina propria of IL-10–eGFP mice were subjected to a screen using candidate soluble mediators previously reported to impact ILC2 activity, T reg cell differentiation, and/or T reg cell function (Cardoso et al, 2017; Duerr et al, 2016; Gao et al, 2009; Josefowicz et al, 2012; Klose et al, 2017; Li et al, 2018; Lim et al, 2016; Mchedlidze et al, 2016; Meylan et al, 2014; Moro et al, 2016; Nussbaum et al, 2013; Ohne et al, 2016; Ricardo-Gonzalez et al, 2018; Ruiter et al, 2015; Symowski and Voehringer, 2019; Wallrapp et al, 2017; Yu et al, 2014; Zheng et al, 2016). In this screen, cells were cultured with the ILC2-activating cytokines IL-25 and IL-33, together with either IL-7 or TSLP, and a candidate soluble mediator.…”

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…The metabolism of ILC2 relies highly on fatty acid metabolism at steady‐state as well as upon T. muris infection on RA‐triggered malnutrition . AhR‐deficient ILC2s show enhanced activity and thereby acceleration of clearance of helminths ( Heligmosomoides polygyrus bakeri ) . This is due to decreased recruitment of the transcriptional determinant Gfi1 to the Il1rl1 locus in genetically induced AhR‐deleted ILC2s.…”

“…Interestingly, the latter population is dependent on ligand‐induced stimulation of AhR, as discussed previously. Whereas ILC3s are supported by AhR stimulation and needed to fight off C. rodentium infection, ILC2s are inhibited by AhR signalling in helminth infections . Retinoic acid is essential for ILC3 activity during C. rodentium infection.…”

The balance of power: innate lymphoid cells in tissue inflammation and repair

“…Ahr ligands enable ILC3 regulation of the commensal microbiota and homeostatic immunity (64). In contrast, cell-intrinsic Ahr inhibits key ILC2 effectors (65). This Ahr dependency establishes a link between dietary nutrients and the balance between ILC2 and ILC3 immunity in the gut.…”