Innate lymphoid cells (ILCs) are lymphocyte-like cells lacking T or B cell receptors that mediate protective and repair functions through cytokine secretion. Among them, type 2 ILC (ILC2) cells are capable of producing type 2 cytokines. We report the existence of an inflammatory (i) ILC2 population responsive to IL-25 that complements IL-33-responsive natural (n) ILC2 cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo, contributing to expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing capacity, providing partial protection against Candida albicans. We propose that iILC2 cells are transient ILC progenitors mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi.

Expression of the transcription factor GATA-3 is strongly associated with T helper type 2 (T(H)2) differentiation, but genetic evidence for its involvement in this process has been lacking. Here, we generated a conditional GATA-3-deficient mouse line. In vitro deletion of Gata3 diminished both interleukin 4 (IL-4)-dependent and IL-4-independent T(H)2 cell differentiation; without GATA-3, T(H)1 differentiation occurred in the absence of IL-12 and interferon-gamma. Gata3 deletion limited the growth of T(H)2 cells but not T(H)1 cells. Deletion of Gata3 from established T(H)2 cells abolished IL-5 and IL-13 but not IL-4 production. In vivo deletion of Gata3 using OX40-Cre eliminated T(H)2 responses and allowed the development of interferon-gamma-producing cells in mice infected with Nippostrongylus brasiliensis. Thus, GATA-3 serves as a principal switch in determining T(H)1-T(H)2 responses.

an IL-1 family member and a specific STAT activator, implying an innate mechanism through which memory CD4 T cells are recruited by an induced cytokine environment. IL-33 ͉ TSLP ͉ IL-18 ͉ STAT5 ͉ T1ST2I L-33, a member of the IL-1 family, is synthesized as a 31-kDa precursor and cleaved in vitro by caspase-1 to a mature 18-kDa form (1). T1ST2, originally identified as an orphan receptor expressed primarily on Th2 and mast cells (2-4), has now been shown to bind to IL-33 and to form a complex with IL-1RAcP (5, 6) that mediates IL-33 signaling (1). IL-33 transduces its effects through the classical IL-1 signaling machinery, including activation of NF-B and MAPKs (1).Administration of IL-33 to mice causes profound alterations in mucosal tissues, including lung, esophageal, and intestinal eosinophilia, and splenomegaly, and enhanced serum IgA and IgE (1). Inhibition of IL-33, either by anti-T1ST2 antibody or T1ST2 immunoglobin, blocks secretion of IL-4, IL-5, and IL-13 and markedly suppresses eosinophilic inflammation in recipients of ovalbumin-specific Th2 cells challenged with ovalbumin (2, 7). T1ST2-deficient mice show a defect in primary response to schistosoma egg antigens (8) and IL-33 treatment at the time of Trichuris muris infection allows susceptible mice to expel the parasite (9).These results indicate an important role for IL-33 and T1ST2 in allergic/parasite-induced inflammatory responses. However, the molecular regulation of T1ST2 expression and how IL-33 mediates its function remain unclear. Here we show that T1ST2 expression by Th2 cells is regulated by GATA3 and STAT5. Further, IL-33 and STAT5 activators such as IL-2, IL-7, and TSLP act synergistically to induce and maintain GATA3 expression. IL-33 then acts on T1ST2-expressing Th2 cells to induce production of IL-13, but not IL-4, in a TCR-independent, NF-B-, and p38-dependent manner. Such TCR-independent IL-13 production by Th2 cells is similar to the previous demonstration by others that treatment of Th1 cells with IL-18 and IL-12 induces IFN␥ production (10). Consistent with these findings, we also show that Th17 cells (11-13) treated with IL-1␤ and a STAT3 activator (IL-6, IL-21, or IL-23) produce IL-17A in a TCR-independent manner. Thus, all 3 effector Th populations respond to an IL-1 family member and a STAT activator with the production of a key effector cytokine, providing a mechanism for innate activation of memory or effector CD4 T cells. Results T1ST2 Expression on Th2Cells. T1ST2 is under tight regulation while IL-1RAcP is broadly expressed. Naïve CD4 T cells do not express detectable T1ST2 (Fig. 1A). Culture under Th2 conditions for 4 days (1xTh2) results in a small fraction of the cells expressing high levels of T1ST2. More Th2 cells express T1ST2 after a second round of priming (2xTh2) and essentially all 3-round primed Th2 cells (3xTh2) express T1ST2 (Fig. 1 A). T1ST2 expression falls strikingly when 3xTh2 cells are ''rested'' in IL-2- (Fig. 1 A and B), IL-7-, or TSLP-containing medium (Fig. 1B). Rested Th2 cells expressing low leve...