FOXP3+ regulatory T cells (Treg 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. The interleukin (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, in response to tissue damage3. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients4,5,6,7, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis8,9,10,11, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-β1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, 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.
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Gene Expression Omnibus
Microarray data have been deposited in the Gene Expression Omnibus under accession number GSE58164.
C.S., K.A., A.C., O.J.H. and F.P. are supported by the Wellcome Trust. F.P. is also supported by the Fondation Louis Jeantet. A.N.H. is supported by a European Molecular Biology Organization long-term fellowship (ALTF 116-2012). P.G.F. is supported by Science Foundation Ireland. M.L. and A.F. are supported by the Volkswagen Foundation (Lichtenberg Program) and BMBF (e:Bio/T-Sys). B.M.J.O. is supported by an Oxford-UCB Pharma Postdoctoral Fellowship. We thank all members of the Oxford Translational Gastroenterology Unit for assistance and support. We are grateful to H. Ferry and K. Alford for essential flow cytometry support and the staff of the University of Oxford for animal care. We are also grateful to D. Baban for conducting microarray hybridizations.