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 6

Altered GCB cell cycling and increased apoptosis in the absence of Tfr cells.

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Altered GCB cell cycling and increased apoptosis in the absence of Tfr c...
(A) WT and MB1-Il10ra–/– mice were sensitized with PCT. On day 36, GCB cells from SPs were stained and analyzed by flow cytometry for light zone (LZ) (CD86) and dark zone (DZ) (CXCR4) marker expression. Representative contour dot plots of GCB DZ/LZ cell staining are shown along with graphs indicating the average ratios of GCB LZ to GCB DZ cells. (B) WT and Bcl6FC mice were sensitized with PCT. On day 36, GCB cells from SPs were stained and analyzed by flow cytometry for LZ and DZ marker expression as in A. Representative contour dot plots of GCB DZ/LZ cell staining are shown along with graphs indicating the average ratios of GCB LZ to GCB DZ cells. Data for A and B are from 1 representative experiment of 2 experiments with 4–5 mice per group. WT and Bcl6FC (C) and MB1-Il10ra–/– (D) mice were sensitized with PCT. On day 36 GCB cells from LNs were stained and analyzed by flow cytometry for viability using eBioscience Fixable Viability Dye. Representative viability stains are shown along with graphs indicating the average percentage of GCB cell death. Data for A and B are from 1 representative experiment of 2 experiments with 4–5 mice per group. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test (A–D).