T follicular regulatory cells and IL-10 promote food antigen–specific IgE
Markus M. Xie, … , Mark H. Kaplan, Alexander L. Dent
Markus M. Xie, … , Mark H. Kaplan, Alexander L. Dent
Published April 7, 2020
Citation Information: J Clin Invest. 2020;130(7):3820-3832. https://doi.org/10.1172/JCI132249.
View: Text | PDF
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

×

Figure 1

Lack of Tfr cells in a food allergy model leads to loss of peanut-specific IgE and decreased anaphylaxis responses.

Options: View larger image (or click on image) Download as PowerPoint
Lack of Tfr cells in a food allergy model leads to loss of peanut-specif...
Peanut allergy was induced with 2 i.g. doses of PCT given 7 days apart, and mice were bled at various time points after sensitization. (A) Schema showing the 36-day timeline, in which serum was tested 28 days after the last sensitization for peanut-specific Abs. (B–D) Control Foxp3-Cre mice (WT) and Bcl6FC mice were sensitized as in A, and day-36 serum was tested for peanut-specific IgE, IgG1, and total IgE (B) or at various time points during and after sensitization as indicated (red arrows in C) (C and D). Data for A and B are from 1 representative experiment of 4 experiments with 4–5 mice per group. Data for C and D are from 1 representative experiment of 2 experiments with 4–5 mice per group. (E) WT and Bcl6FC mice sensitized as in A were analyzed for anaphylactic responses on day 36. Nonsensitized WT and Bcl6FC mice were used as negative controls. Data for E were pooled from 2 experiments with 3–7 mice per group (n = 6–14). (F and G) Control Bcl6fl/fl (WT) mice and CD4-Bcl6–cKO mice were sensitized as shown in A. (F) Day-36 serum was tested for peanut-specific IgE, IgG1, and total IgE. (G) Mice were tested for anaphylaxis as described in E. Data for F are from 1 representative experiment of 3 experiments with 4–5 mice per group. Data for G are from 1 representative experiment of 2 experiments with 3–5 mice per group. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA with Holm-Šidák multiple comparisons test (B, D, and F) or 2-way ANOVA with Tukey’s multiple comparisons test (E and G).