T fr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1–dependent activation of T fh cells

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Follicular regulatory T (Tfr) cells from lymph node germinal centers control follicular helper T (Tfh) cell-dependent B cell activation. These scarce cells, often described and purified as CD25⁺ cells, are thought to be derived from thymic regulatory T (Treg) cells. However, we observed that mouse Tfr cells do not respond to interleukin-2 (IL-2), unlike Treg cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that Tfr cells are actually CD25⁻, in mice and humans. Moreover, Tfr cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25⁺ cells resulted in contamination with Treg cells. Transcriptome studies of CD4⁺CXCR5⁺PD-1⁺Bcl6⁺Foxp3⁺CD25⁻ Tfr cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas Tfh cells express the IL-1R1 agonist receptor. IL-1 treatment expanded Tfh cells in vivo and activated their production of IL-4 and IL-21 in vitro. Tfr cells suppressed the IL-1-induced activation of Tfh cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the Tfh cell control of B cell responses and an IL-2/IL-1 dichotomy for Treg cell control of effector T cells versus Tfr cell control of Tfh cells.