T follicular regulatory cells and IL-10 promote food antigen–specific IgE
Markus M. Xie, Qiang Chen, Hong Liu, Kai Yang, Byunghee Koh, Hao Wu, Soheila J. Maleki, Barry K. Hurlburt, Joan Cook-Mills, Mark H. Kaplan, Alexander L. Dent
Markus M. Xie, Qiang Chen, Hong Liu, Kai Yang, Byunghee Koh, Hao Wu, Soheila J. Maleki, Barry K. Hurlburt, Joan Cook-Mills, Mark H. Kaplan, Alexander L. Dent
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Research Article Immunology

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

Abstract

Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell–deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre Ptenfl/fl mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanut-specific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development.

Authors

Markus M. Xie, Qiang Chen, Hong Liu, Kai Yang, Byunghee Koh, Hao Wu, Soheila J. Maleki, Barry K. Hurlburt, Joan Cook-Mills, Mark H. Kaplan, Alexander L. Dent

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Figure 7

Blimp1-controlled Tfr cell–derived IL-10 is required for peanut-specific IgE production.

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Blimp1-controlled Tfr cell–derived IL-10 is required for peanut-specific...
(A) Il10 mRNA levels in Tregs or Tfr cells isolated from naive or PCT-sensitized WT mice on day 0 (naive) and day 15 as in the model shown in Figure 1. (B) Design for WT/Bcl6FC and Bcl6FC/Blimp1FC BM chimeras. (C–E) Mice generated as in B were sensitized with PCT. Then on day 36, (C) Tfh and Tfr cells were isolated by FACS, and Il10 expression was analyzed by qPCR; (D) Tfh, Tfr, and GCB cells from LNs were stained and analyzed by flow cytometry as in Figure 2; and (E) peanut-specific IgE and IgG1 titers from day-36 serum obtained from mice after PCT sensitization were measured. Data for A were pooled from 3 different cell sorts with 2–4 mice per sort (n = 6–10). Data for C–E are from 1 representative experiment of 2 experiments with 3–5 mice per group after PCT sensitization. (F) Scheme for blockade of IL-10R during PCT sensitization in WT and Bcl6FC mice. Numbers indicate the specific days for i.p. anti–IL-10R Ab treatment, i.g. PCT gavage, blood sampling, and anaphylaxis. Control mice received anti–HRP-IgG1 Ab. (G) Peanut-specific IgE (day 15) and IgG1 (day 29) titers from serum obtained from control and anti–IL-10R–treated mice as described in F. Data for F and G are from 1 representative experiment of 2 experiments with 3–4 mice per group. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA with Tukey’s multiple comparisons test (A, C, and G) or 2-tailed Student’s t test (D).