The Alarmin IL-33 Promotes Regulatory T Cell Function in the Intestine

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 T(reg) cells acquire tissue-specific adaptations that facilitate their survival and function(1); however, key host factors controlling the T(reg) response in the intestine are poorly understood. 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 following tissue damage(3). Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease (IBD) patients(4-7) 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 colitis(8-11) but its contribution to chronic inflammation remains ill defined. Here we show that the IL-33 receptor ST2 is preferentially expressed on colonic T(reg) (cT(reg)) cells, where it promotes T(reg) function and adaptation to the inflammatory environment. IL-33 signaling into T cells stimulates T(reg) responses in several ways. Firstly, it enhances transforming growth factor-β1 (TGF-β(1)) mediated differentiation of T(reg) cells and secondly, it provides a necessary signal for T(reg) accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of IBD, 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.