Expression of IL-1R2 by T follicular regulatory cells prevents the exacerbation of allergy by blocking their IL-1-dependent proliferation

The antibody response is regulated by follicular T helper (Tfh) and regulatory (Tfr) cells that control the germinal center (GC) reaction. Recent research has shown that Tfh/Tfr have a unique pattern of IL-1 receptor expression. We investigated the mechanisms by which this IL-1 axis in GCs could regulate the allergic response.

To study this, we generated CD4 ^cre IL-1R1 ^lox mice, specifically lacking IL-1R1 expression in T cells and FoxP3 ^cre IL-1R2 ^lox mice, specifically lacking IL-1R2 expression in Tfr cells. The conditional knockout mice were compared to their respective control mice in a model of ovalbumin (OVA) sensitization and anaphylaxis, and a phenotypic and functional characterization of humoral and cellular responses was performed.

While CD4 ^cre IL-1R1 ^lox mice showed little phenotypic changes, FoxP3 ^cre IL-1R2 ^lox mice were highly susceptible to allergic anaphylaxis and generated an increase in IgE responses that promoted basophil degranulation. Additionally, FoxP3 ^cre IL-1R2 ^lox mice displayed significantly reduced OVA-specific IgG responses, limiting their ability to control allergy via the inhibitory IgG receptor FcγRIIb. Although FoxP3 ^cre IL-1R2 ^lox mice showed an overall increase in splenic T and B cell numbers, they were unable to efficiently generate proliferating GC B cells. Upon ex vivo IL-1β and/or OVA re-stimulation, we observed a striking IL-1R1-dependent activation and proliferation of Tfr cells in FoxP3 ^cre IL-1R2 ^lox splenocytes, that was neither observed in Tregs nor in Tfh. At the same time, B cell proliferation upon re-stimulation was suppressed.

These findings suggest that IL-1R2 expression on Tfr cells prevents allergy by limiting excessive Tfr activation and suppressing the IgG/IgE ratio.