Tfr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1–dependent activation of Tfh cells

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