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

The alarmin interleukin-33 is constitutively expressed at barrier sites and released in response to tissue damage; here, the IL-33 receptor ST2 is shown to be preferentially expressed on colonic regulatory T cells, where it promotes regulatory T-cell function and adaptation to the inflammatory tissue environment. Interleukin-33 promotes T reg cell function Interleukin-33 (IL-33) is an 'alarmin', constitutively expressed at barrier sites and released in response to tissue damage where it recruits components of the repair response. This study in two mouse models of colitis shows that the IL-33 receptor ST2 is preferentially expressed on colonic regulatory T cells, where it promotes regulatory T-cell function and adaptation to the inflammatory tissue environment. IL-33 is negatively regulated by the pro-inflammatory cytokine IL-23, suggesting that the balance between IL-33 and IL-23 could be an important controller of intestinal immune responses. 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 the T 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 , 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 colitis 8 , 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 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)-β 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 bo