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

Abstract

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.

Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs

“…effector macrophages by sialylated Fc critically depends on production and secretion of IL-33 (29). Recent findings have indicated that IL-33 has a positive effect on T reg -cell stimulation and activation (31,32) and thereby contributes to the suppression of inflammation in a mouse model of experimental colitis (33). To test the possibility that sFc-induced production of IL-33 may also contribute to T reg -cell stimulation, we confirmed that naïve CD4 + T cells isolated from C57BL/6 wild-type mice, cultured for 3 d in the presence of anti-CD3 and anti-CD28 antibodies and TGF-β to specifically drive T reg -cell differentiation and then treated with IL-33, had a synergistic effect on T reg -cell differentiation as well as on Foxp3 expression (Fig.…”

Unstable FoxP3 + T regulatory cells in NZW mice

“…Interestingly, the relative dearth of Treg cells was absent in the NZW BM. Several groups have described distinct Treg subpopulations in the colonic lamina propria (LP), which differ in their origin, relation to the gut microbiota, and expression of key transcription factors (23,(32)(33)(34)(35). Treg cells were found in low proportions in the NZW colonic LP (Fig.…”

“…Cytokines-IL-2 foremost-are thought to be the main controllers of Treg proportions and numbers (15)(16)(17)(18)(19)(20)(21)(22), although the relative importance of these controllers varies with location and subphenotype [e.g., the alarmin IL-33 has a more profound role in tissue Tregs (21)(22)(23)]. Perhaps surprisingly, in light of this apparently tight control, there is a wide range of variation in Treg proportions, with several studies having observed up to fourfold variation in the blood of healthy humans (e.g., refs.…”

The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation

“…31 The "alarmin" IL-33/ST2 axis has recently been delineated to play a key role in the loss of epithelial integrity caused by microbial translocation of the mucosal barrier in mice and humans. [32][33][34][35] Despite this relevant axis, an impact of the microbiota remains a less well established and controversial risk factor for aGVHD pathogenesis. 36,37 In conclusion, this study highlights the potentially detrimental role of ATB in aGVHD severity and in OS.…”