Alarmin(g) control

IL-33 ... promotes T_Reg cell function in the intestine

Regulatory T (T_Reg) cells expressing the transcription factor forkhead box P3 (FOXP3) are important for maintaining immune homeostasis in the intestine, but the key factors that control T_Reg cell activity at this site are poorly defined. Now, Fiona Powrie and colleagues show that interleukin-33 (IL-33) — which is an alarmin produced in response to tissue damage — promotes T_Reg cell function in the intestine.

Credit: NPG/S.Bradbrook

The authors set out to identify potential tissue-specific regulators of colonic T_Reg cells; mRNA expression profiles of T_Reg cells from the mesenteric lymph nodes and the colon of mice showed that one of the genes that was most highly upregulated in colonic T_Reg cells was Il1rl1, which encodes the IL-33 receptor ST2 (also known as IL-1 receptor-like 1). ST2⁺ T_Reg cells are abundant in the intestine, so the authors hypothesized that IL-33 might modulate T_Reg cell differentiation. Naive CD4⁺ T cells were isolated from Foxp3^gfp reporter mice and activated in the presence of transforming growth factor β1 (TGFβ1). The addition of IL-33 to these cultures increased the percentage and number of FOXP3-expressing cells, but only in the presence of TGFβ1. Thus, IL-33 is a novel cofactor for TGFβ1-mediated in vitro generation of T_Reg cells.

Next, the authors investigated whether IL-33 has a role in the in vivo proliferation of thymus-derived T_Reg cells, which constitute a substantial proportion of the ST2⁺ colonic T_Reg cells. Indeed, IL-33 induced proliferation in splenic T_Reg cells but not in effector T cells. Furthermore, Il1rl1^−/− T_Reg cells showed impaired proliferation after injection of IL-33 into chimeric mice that contained a mixture of wild-type and Il1rl1^−/− haematopoietic cells. Hence, IL-33 promotes the proliferation and accumulation of thymus-derived T_Reg cells in vivo.

The T-cell-specific transcription factor GATA-binding protein 3 (GATA3) is known to be important for T_Reg cell stability and function, and to regulate ST2 expression in T helper 2 (T_H2) cells. Hence, the authors investigated the role of GATA3 in IL-33-mediated regulation of intestinal T_Reg cells and found that GATA3 was phosphorylated after IL-33 stimulation of TGFβ1-activated naive CD4⁺ T cells. This stimulation induced the recruitment of GATA3 and RNA polymerase II to the Foxp3 promoter, which indicates that IL-33 regulates Foxp3 expression. In addition, the authors found that GATA3 was recruited to the Il1rl1 enhancer element. Thus, IL-33 seems to have a role in Foxp3 induction, as well as in promoting the expression of its own receptor.

Using the T cell transfer model of colitis, the authors examined the ability of Il1rl1^−/− T_Reg cells to protect mice from disease; naive T cells were injected into Rag1^−/− mice (which lack the gene encoding recombination-activating gene 1) either alone, or together with wild-type or Il1rl1^−/− T_Reg cells. The ability of Il1rl1^−/− T_Reg cells to prevent colitis was substantially impaired, which indicates that IL-33 signalling is important for the suppressive function of T_Reg cells in vivo.

Finally, the authors examined whether IL-23 — which can promote intestinal inflammation by inhibiting T_Reg cell differentiation — limits T cell responsiveness to IL-33. Indeed, the ability of IL-33 to promote FOXP3 expression in vitro in the presence of TGFβ1 was abolished after the addition of IL-23. The authors showed that IL-23 prevents T cells from responding to IL-33 by inhibiting ST2 expression and ST2 signal transduction.

Taken together, this study shows that IL-33 produced in response to tissue damage can enhance local intestinal T_Reg cell responses. Notably, IL-23 can limit this regulatory mechanism by inhibiting the responsiveness of T_Reg cells to IL-33.