Abstract
Follicular helper (TFH) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of TFH numbers maintains self tolerance. We describe a population of Foxp3+Blimp-1+CD4+ T cells constituting 10–25% of the CXCR5highPD-1highCD4+ T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (TFR) cells share phenotypic characteristics with TFH and conventional Foxp3+ regulatory T (Treg) cells yet are distinct from both. Similar to TFH cells, TFR cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, TFR cells originate from thymic-derived Foxp3+ precursors, not naive or TFH cells. TFR cells are suppressive in vitro and limit TFH cell and germinal center B cell numbers in vivo. In the absence of TFR cells, an outgrowth of non–antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the TFH differentiation pathway is co-opted by Treg cells to control the germinal center response.
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Acknowledgements
We thank X. Hu and J. Fitch for technical assistance, D. Zotos for help with experiments not included in this manuscript, A. Rudensky for kind provision of Foxp3gfp mice and M. Espeli for helpful discussions. This work was funded by National Health and Medical Research Council program and project grants to C.G.V., a Vlaams Instituut voor Biotechnologie principal investigator grant to A.L. and a Wellcome Trust Programme grant (083650/Z/07/Z) to K.G.C.S. M.A.L. is supported by an EMBO post-doctoral long-term fellowship (ALTF 1041-2009) and a Raymond and Beverly Sackler Junior Research Fellowship, Churchill College, Cambridge; C.G.V. is supported by a Viertel Senior Medical Research Fellowship; K.G.C.S. is supported by a Lister Prize Fellowship; T.F.R. is supported by the National Institute of Health Research, Cambridge Biomedical Research Centre; and A.L. is supported by a Juvenile Diabetes Research Foundation Career Development Fellowship and a Marie Curie Reintegration Grant Fellowship.
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M.A.L. designed and performed experiments, analyzed the data and wrote the manuscript. W.P. performed experiments. S.K.L. performed experiments. A.K. contributed Blimp-1 chimera experiments and reviewed the manuscript. S.K. contributed confocal microscopy images. T.F.R. performed bioinformatic analyses. M.S. performed qRT-PCR experiments. D.P.D., L.B. and J.J.H. performed experiments. S.F. contributed confocal microscopy images and reviewed the manuscript. A.L. designed experiments and reviewed the manuscript. K.G.C.S. designed experiments, wrote the manuscript and supervised the study. C.G.V. designed experiments, wrote the manuscript and supervised the study.
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Supplementary Figures 1–11, Supplementary Table 2 and Supplementary Methods. (PDF 1239 kb)
Supplementary Table 1
Differentially expressed genes in TFR cells (XLS 361 kb)
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Linterman, M., Pierson, W., Lee, S. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17, 975–982 (2011). https://doi.org/10.1038/nm.2425
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DOI: https://doi.org/10.1038/nm.2425
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