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Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions

Abstract

Foxp3+ regulatory T (Treg) cells suppress different types of immune responses to help maintain homeostasis in the body. How Treg cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of Treg cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on Treg cells depends on Bcl-6. These CXCR5+Bcl-6+ Treg cells are absent in the thymus but can be generated de novo from CXCR5Foxp3+ natural Treg precursors. A lack of CXCR5+ Treg cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in Treg cells that drives the development of follicular regulatory T (TFR) cells that function to inhibit the germinal center reactions.

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Figure 1: CXCR5+ Treg cells co-express Bcl-6 and expand upon immunization.
Figure 2: Generation of CXCR5+Foxp3+ T cells requires Bcl-6.
Figure 3: Characterization of CXCR5+Foxp3+ T cells.
Figure 4: Bcl-6+CXCR5+ Treg cells are generated from CXCR5 natural Treg cells in the periphery.
Figure 5: Uncontrolled germinal center reactions in scurfy mice.
Figure 6: Both Cxcr5−/− Treg and Bcl-6−/− Treg were inefficient in controlling germinal center reactions.

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Acknowledgements

We thank R. Dalla-Favera (Columbia University) for the Bcl-6-deficient mice, A. Rudensky (Memorial Sloan-Kettering Cancer Center) for Foxp3GFP reporter mice, D. Tran (University of Texas at Houston) for the antibody to Helios, Z. He, K. Ramirez and K. Dwyer for help with cell sorting and the entire Dong lab for their help. This work was supported by research grants from the US National Institutes of Health (C.D., to R.I.N. and to S.S.N.), the Leukemia and Lymphoma Society (C.D.), the MD Anderson Cancer Center (C.D.), the American Heart Association (Y.C.), Doris Duke Charitable Foundation Clinical Scientist Development Award (S.S.N.) and China Ministry of Science and Technology Protein Science Key Research Project (X.Z., H.F. and C.D.).

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Y.C. and C.D. designed the experiments and wrote the manuscript; Y.C., S.T., F.C., R.I.N., G.J.M., S.R., Y.-H.W., H.L., J.M.R., X.Z., H.F. and Z.L. performed experiments and analyzed data; S.S.N. designed and analyzed human sample data.

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Correspondence to Yeonseok Chung or Chen Dong.

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The authors declare no competing financial interests.

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Chung, Y., Tanaka, S., Chu, F. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17, 983–988 (2011). https://doi.org/10.1038/nm.2426

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