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bioRxiv · 10.1101/2024.08.29.610028

Expression of IL-1R2 by Tfr prevents their IL-1-dependent proliferation and the exacerbation of allergy

Engeroff, P.·Belbezier, A.·Vaineau, R.·Fourcade, G.·Lujan, H. D.·Bellier, B.·Graff-Dubois, S.·Klatzmann, D.
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Abstract

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 CD4creIL-1R1lox mice, specifically lacking IL-1R1 expression in T cells and FoxP3creIL-1R2lox 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 CD4creIL-1R1lox mice showed little phenotypic changes, FoxP3creIL-1R2lox mice were highly susceptible to allergic anaphylaxis and generated an increase in IgE responses that promoted basophil degranulation. Additionally, FoxP3creIL-1R2lox mice displayed significantly reduced OVA-specific IgG responses, limiting their ability to control allergy via the inhibitory IgG receptor Fc{gamma}RIIb. Although FoxP3creIL-1R2lox 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-1{beta} and/or OVA re-stimulation, we observed a striking IL-1R1-dependent activation and proliferation of Tfr cells in FoxP3creIL-1R2lox 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.

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Engeroff, P., Belbezier, A., Vaineau, R., Fourcade, G., Lujan, H. D., Bellier, B., Graff-Dubois, S., Klatzmann, D.. 2024-08-30. Expression of IL-1R2 by Tfr prevents their IL-1-dependent proliferation and the exacerbation of allergy. https://doi.org/10.1101/2024.08.29.610028

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