IL-1β Signaling Modulates T Follicular Helper and Regulatory Cells in Human Lymphoid Tissues

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IL-1β Signaling Modulates T Follicular Helper and Regulatory Cells in Human Lymphoid Tissues

Authors

Vaineau, R.; Jeger-Madiot, R.; Ali-Moussa, S.; Prudhomme, L.; Debarnot, H.; Coatnoan, N.; Dubois, J.; Binvignat, M.; Vantomme, H.; Gouritin, B.; Fourcade, G.; Engeroff, P.; Belbezier, A.; Luscan, R.; Denoyelle, F.; Lorenzo, R.; Ribet, C.; Rosenzwajg, M.; Bellier, B.; Klatzmann, D.; Tchitchek, N.; Graff-Dubois, S.

Abstract

Background: Dysregulation of the T follicular helper (Tfh) and T follicular regulatory (Tfr) homeostasis in the germinal center (GC) can result in antibody-mediated autoimmunity. While interleukin-1{beta} (IL-1{beta}) has been shown to be an important modulator of the GC response in animal models via the expression of IL-1 agonist (IL-1R1) and antagonist (IL-1R2) receptors on follicular T cells, such regulation has not yet been studied in humans. Methods: We investigated Tfh and Tfr phenotypes in human secondary lymphoid organs - namely tonsils, spleens, and mesenteric lymph nodes - using flow cytometry, single-cell transcriptomics, and in vitro cell culture. We also benchmarked our findings with a cohort of patients with autoimmune and inflammatory diseases. Results: We found that Tfh and Tfr cells exhibit organ-specific phenotypes related to their activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 was linked to the emergence of a unique activated Tfr subset that combines features of both Treg and GC-Tfh cells. Single-cell transcriptomics and in vitro studies showed that IL-1{beta} signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1{beta} resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1{beta} and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1{beta} signaling, and the Tfr/Tfh balance. Conclusions: Our study underscores the pivotal role of IL-1{beta} in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1{beta} signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.

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