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...

IgE-mediated activation of mast cells and basophils contributes to protective immunity against helminths but also causes allergic responses. The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells. Here, we used next generation sequencing to uncover a striking overlap between the IgE and IgG1 repertoires in helminth-infected or OVA/alum-immunized wild-type BALB/c mice. The memory IgE response after secondary infection induced a strong increase of IgE+ plasma cells in spleen and lymph nodes. In contrast, germinal center B cells did not increase during secondary infection. Unexpectedly, the memory IgE response was lost in mice where the extracellular part of IgG1 had been replaced with IgE sequences. Adoptive transfer studies revealed that IgG1+ B cells were required and sufficient to constitute the memory IgE response in recipient mice. T cell-derived IL-4/IL-13 was required for the memory IgE response but not for expansion of B cells from memory mice. Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells. Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders.

Intestinal epithelial cells (IECs) constitute an important barrier between host and pathogen. Immune mechanisms that provide protection against gastrointestinal helminths often require IL-4Rα-induced activation of STAT6-regulated genes in IECs. However, it is not known whether STAT6 activation in IECs enhances protective immunity against helminths. Furthermore, the regulation of proliferation and differentiation processes of the intestinal epithelium by IEC-intrinsic STAT6 signaling remains unclear. To address these questions, we generated mice with specific expression of a constitutively active version of STAT6 in IECs. These VillinCre_STAT6vt mice show accumulation of secretory IECs, increased proliferation of IECs and lengthening of the small intestine. They rapidly expelled Nippostrongylus brasiliensis worms even in the absence of T cells. Furthermore, primary infection with Heligmosomoides polygyrus resulted in larval trapping in the submucosa and the fecundity of adult worms was severely impaired. Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths.Mucosal Immunology (2019) 12:413-424; https://doi.