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

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Science Immunology  08 Sep 2017:
Vol. 2, Issue 15, eaan0368
DOI: 10.1126/sciimmunol.aan0368

Immune regulation in the germinal center

Unregulated production of antibodies may contribute to the development of autoimmunity. Follicular regulatory T (Tfr) cells are thought to limit the germinal center (GC) reaction and to reduce antibody production within B cell follicles in both humans and mice, yet how Tfr cells control the GC reaction remains unclear. Ritvo et al. closely characterize Tfr cells and identify these cells as a rare population of CD4+CXCR5+PD-1+Foxp3+ cells that do not express CD25 and do not respond to interleukin-2. When compared with follicular helper T (Tfh) cells and regulatory T cells, Tfr cells clustered with Tfh cells. Moreover, they expressed decoy molecules for the interleukin-1 signaling pathway, suggesting a mechanism for the suppression of Tfh cells.


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.

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