Foxp3+ regulatory T cells are abundant in the intestine where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function1; however, key host factors controlling the Treg response in the intestine are poorly understood. IL-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites2 where it functions as an endogenous danger signal or alarmin following tissue damage3. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease (IBD) patients4-7 suggesting a role for this cytokine in the pathogenesis of IBD. In the intestine, both protective and pathologic roles for IL-33 have been described in murine models of acute colitis8-11 but its contribution to chronic inflammation remains ill defined. Here we show that the IL-33 receptor ST2 is preferentially expressed on colonic Treg (cTreg) cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signaling into T cells stimulates Treg responses in several ways. Firstly, it enhances transforming growth factor-β1 (TGF-β1) mediated differentiation of Treg cells and secondly, it provides a necessary signal for Treg accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of IBD, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.

IL-1β promotes chronic intestinal inflammation through recruitment of granulocytes, activation of ILCs, accumulation of pathogenic T cells, and promotion of Th17 responses.

The aryl hydrocarbon receptor (AHR) recognises xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors1–4 and is important for maintenance of homeostasis at mucosal surfaces. AHR activation induces cytochrome P4501 (CYP1) enzymes, which oxygenate AHR ligands, leading to their metabolic clearance and detoxification5. Thus, CYP1 enzymes appear to play an important feedback role that curtails the duration of AHR signalling6, but it remains elusive whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 depletes the reservoir of natural AHR ligands, generating a quasi AHR-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells (IECs) resulted in loss of AHR-dependent type 3 innate lymphoid cells (ILC3) and T helper 17 (Th17) cells and increased susceptibility to enteric infection. The deleterious effects of excessive AHR ligand degradation on intestinal immune functions could be counter-balanced by increasing the intake of AHR ligands in the diet. Thus, our data indicate that IECs serve as gatekeepers for the supply of AHR ligands to the host and emphasise the importance of feedback control in modulating AHR pathway activation.