TFR-derived IL-4 is required for antigen-specific IgE but not antigen-specific IgG1 production in a peanut allergy model

Abstract

Abstract T follicular regulatory cells (TFR) have been shown to regulate antibody production in germinal centers. Cytokine IL-4 controls the class-switching of IgG1 and IgE and is associated with the type II immune response. Though T follicular help cells (TFH) have been identified as a source of IL-4, whether and how IL-4 from TFR cells regulate antibodies including IgE remains unknown. Utilizing a food allergy model in which mice are sensitized using peanut extract and cholera toxin through oral gavage, we found that peanut-specific IgE but not IgG1 is absent with in vivo anti-IL-4Rα antibody treatment, while total IgE is also affected. This differential requirement for IL-4 is further validated using Il4-heterzygous mice, suggesting that IL-4 haploinsufficiency only impairs IgE production. Additionally, the number of germinal center B cells were not reduced in both models. To determine the role of IL-4 from TFR cells specifically, bone marrow chimera mice were constructed in which IL-4 is deficient in TFH and/or TFR cells. Both peanut-specific IgG1 and IgE were impaired when IL-4 is deficient in both TFH and TFR cells, while only peanut-specific IgE is almost absent when IL-4 is deficient in TFR cells. In another mouse model, where mice are immunized with OVA plus alum, the differential roles of IL-4 in IgE and IgG1 production are recapitulated. In conclusion, switching to IgE requires a stronger IL-4 signal compared to IgG1, and TFR cell-derived IL-4 plays a critical role in switching to IgE but not to IgG1. Supported by grants from NIH (R01AI132771)