Innate lymphoid cells (ILCs) reside at mucosal surfaces and control immunity to intestinal infections. Type 2 innate lymphoid cells (ILC2s) produce cytokines such as IL-5 and IL-13, are required for immune defense against helminth infections, and are involved in the pathogenesis of airway hyperreactivity. Here, we have investigated the role of the transcription factor GATA-3 for ILC2 differentiation and maintenance. We showed that ILC2s and their lineage-specified bone marrow precursors (ILC2Ps), as identified here, were characterized by continuous high expression of GATA-3. Analysis of mice with temporary deletion of GATA-3 in all ILCs showed that GATA-3 was required for the differentiation and maintenance of ILC2s but not for RORγt(+) ILCs. Thus, our data demonstrate that GATA-3 is essential for ILC2 fate decisions and reveal similarities between the transcriptional programs controlling ILC and T helper cell fates.

Significance Gastrointestinal worms (helminths) infect more than 2 billion people, and vaccines are not yet available. Helminths elicit a type 2 immune response characterized by high serum IgE levels and increased numbers of IL-4– or IL-13–secreting effector cells including Th2 cells, eosinophils, basophils, and type 2 innate lymphoid cells. We determined the mechanism by which basophils contribute to protection against secondary infections with gastrointestinal helminths. Here we demonstrate that basophils are recruited into the small intestine of infected mice and orchestrate the local type 2 immune response in this tissue. Basophil-mediated protection required the presence of IgE and the expression of activating Fc receptors and IL-4/IL-13 in basophils. These findings could help the development of new vaccination strategies against helminths.

Infection with helminths and exposure to antigens induce a strong type 2 immune response resulting in the secretion of the cytokines IL-4 and IL-13 by CD4 + T cells and several innate cell types. IL-4 and IL-13 promote class switch recombination to IgG1 and IgE while their role for germinal center (GC) formation is poorly understood. We found a dramatic reduction in the numbers of GC B cells when investigating different type 2 immune responses in IL-4/IL-13-deficient mice. IL-4/IL-13 from T cells locatedAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe cytokines IL-4 and IL-13 contribute to protective immunity against gastrointestinal helminths but also cause pathological side effects seen in atopic diseases. it remains unclear to what extent innate IL-4/IL-13-expressing cell types may also contribute to this process.CSR and affinity maturation of the antibody response to T-dependent antigens usually occurs in germinal centers (GCs). GCs form dynamic structures composed of the light zone where GC B cells undergo selection by interacting with T FH cells and follicular dendritic cells (FDCs) and the dark zone where GC B cells mainly proliferate. The role of the cytokine IL-21 secreted by T FH cells for GC development and subsequent generation of memory B cells is well understood. However, it remains controversial whether other cytokines such as IL-4 and IL-13 might also be critical beyond induction of CSR. Previous studies on the role of IL-4 for GC formation led to inconclusive results. Depending on the kind of adjuvant used IL-4-deficient mice were reported to develop either a normal [1,2], enhanced [3], or diminished [4,5] GC response in LNs after OVA immunization.To conclusively address the role of IL-4/IL-13 for B-cell responses, we used different stimulation protocols to generate type 1 and type 2 immune responses. We found that absence of IL-4/IL-13 impairs formation of GC during type 2 immune responses such as Nippostrongylus brasiliensis (Nb) infection, immunization with OVA/alum or sheep red blood cells (SRBCs) but not during type 1 immune response to lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). Using conditional IL-4/IL-13-deficient (4-13Tko) mice, we identified T cells to be the essential source of IL-4/IL-13 for the GC response. Our results further indicate that IL-4/IL-13 secretion from T cells localized outside B-cell follicles is sufficient for GC formation and IgE-CSR and that STAT6 signaling in B cells is required for GC formation. Results T-cell-derived IL-4/IL-13 promotes GC formation during type 2 immunityWe used infection with Nb to induce a strong type 2 immune response in order to define the roles of IL-4/IL-13 in the activation of B cells in secondary lymphoid organs. Histological analysis of draining LNs on day 12 after Nb infection revealed that GC formation was severely impaired in Nb-infected IL-4/IL-13-deficient (4-13ko) mice compared to WT mice (Fig. 1A). By analyzing GC B c...