Production of Peanut-Specific IgE in a Food Allergy Model Is Promoted by T Follicular Regulatory Cells Via an IL-10-Dependent Pathway

Abstract

Abstract T follicular regulatory (TFR) cells are a specialized subset of Foxp3+ T cells found within the germinal center (GC) reaction and its role remains controversial. Here, we have used a peanut allergy model in mice to examine the role of TFR cells in controlling the production of antigen-specific IgE and IgE-controlled anaphylaxis. Using a mouse model with a specific loss of TFR cells (Foxp3-cre Bcl6-flox mice), we found TFR cells play an essential role in promoting and maintaining GC B cells, IgE production and anaphylaxis. Compared to control mice, TFR-deficient mice lacked circulating peanut-specific IgE four weeks after the priming period and anaphylactic responses were significantly weakened. The loss of IgE in TFR-deficient mice coincided with a marked decrease in GC B cells and peanut-specific IgG1. Similarly, deletion of regulatory T cells using FOXP3DTR mice abolished peanut-specific IgE and IgG1 responses. We identified a positive role for TFR cells in the IgE response using Foxp3-cre Pten-flox mice, which have augmented TFR cell responses, higher peanut-specific IgE and increased GC B cells. Mechanistically, TFR cells require Blimp1 controlled IL-10 to promote GC B cell survival and IgE production. Further studies using mice deficient of IL-10Ra (Mb1-cre Il10ra-flox mice) showed IL-10 signaling was pivotal for GC B and Ab responses. Blocking IL-10 signals in vivo mimicked the loss of IgE levels in TFR-deficient mice and rescued mice from anaphylaxis. Our data unexpectedly show that TFR cells have a critical helper function in the production of GC-dependent IgE, in part by producing IL-10. These studies have provided greater understanding of how allergic immune responses are controlled by the GC reaction.