Tfr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1–dependent activation of Tfh cells
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.
Abstract
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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Supplementary Material
Summary
Materials and Methods
Fig. S1. Representative flow cytometry gating for Tfol cells.
Fig. S2. IL-2 increases the number of splenic Treg cells.
Fig. S3. Expression of CD25 on Tfr and Tfh cells in three different genetic backgrounds.
Fig. S4. Tfh and Tfr cells have similar expressions of Bcl6 and CD25.
Fig. S5. Clustering of Treg, Tfr, and Tfh cells based on the expression of the entire 545-gene set from the NanoString mouse immunology panel.
Fig. S6. Cytokines, CD40L, and OX40 expression of Tfr, Treg, and Tfh cells.
Fig. S7. IL-1R2 and OX40 expression of Tfr, Treg, Teff, and Tfh cells.
Fig. S8. IL-1β production in coculture of B and Tfh cells.
Fig. S9. GCB representative gating after INS or OVA immunization.
Table S1. Exact P values of the asterisk symbols shown in figures.
Source data (Excel file)
Resources
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Science Immunology
Volume 2 | Issue 15
September 2017
September 2017
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Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 24 February 2017
Accepted: 19 July 2017
Acknowledgments
We are grateful to B. Gouritin for help in cell sorting, to P.-A. Vinot for advice regarding ELISA assays, and to W. Chaara for advice regarding gene expression analysis. We thank the Institut Curie Genomic Platform for advising and performing the NanoString experiment, G. Lebreton and colleagues from the Cardio-Thoracic Surgery Department of the Pitié-Salpétrière Hospital for providing the human tissues, F. Tankere from the Otolaryngology Department of the Pitié-Salpétrière Hospital for providing the human tonsils, and V. Kuchroo and B. Malissen for the mice provided. Funding: P.-G.G.R. is a doctoral fellow of the “Ecole de l’Inserm Liliane Bettencourt” and was sponsored by Servier. L.F. was funded by a “DIM Région Ile de France” doctoral fellowship. The work of D.K., E.M.-F., G.C., V.Q., G.F. and F.B. was funded by Assistance Publique–Hôpitaux de Paris, INSERM, Sorbonne Université–UPMC (Paris 6), as well as by LabEx Transimmunom (ANR-11-IDEX-0004-02) and European Research Council Advanced Grant TRiPoD (322856) (to D.K.). Author contributions: P.-G.G.R., G.C., F.B., G.F., and L.F. performed the mouse experiments. P.-G.G.R. performed analyses, including statistical analysis. V.Q. performed the experiment on human samples and analyses, including statistical analysis. P.-G.G.R., G.C., E.M.-F., and D.K. conceived the experiments. P.-G.G.R., E.M.-F., and D.K. wrote the manuscript, with input from all authors. D.K. conceived, supervised, and obtained funding for the entire study. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.
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European Research Council: award303608, 322856
Agence Nationale de la Recherche: award303607, ANR-11-IDEX-0004-02
Fondation Bettencourt Schueller: award303609
Région Ile-De-France: award303610
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