The alarmin IL-33 promotes regulatory T-cell function in the intestine

FOXP3+ regulatory T cells (T-reg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that T-reg cells acquire tissue-specific adaptations that facilitate their survival and function(1); however, key host factors controlling theT(reg) response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites(2), where it functions as an endogenous danger signal, or alarmin, in response to tissue damage(3). Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients(4-7), 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 colitis(8-11), 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 T-reg cells, where it promotes T-reg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates T-reg responses in several ways. First, it enhances transforming growth factor (TGF)-beta 1-mediated differentiation of T-reg cells and, second, it provides a necessary signal for T-reg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained T-reg 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.