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

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-1β (IL-1β) 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-1β signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1β resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1β signaling, and the Tfr/Tfh balance. Conclusions Our study underscores the pivotal role of IL-1β in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1β signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.