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Foxp3+ follicular regulatory T cells control the germinal center response

Nature Medicine volume 17, pages 975–982 (2011)Cite this article

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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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Figure 1: A proportion of CXCR5highPD-1highCD4+ cells express the transcription factor Foxp3.
Figure 2: TFR cells require the same differentiation cues as TFH cells for their development.
Figure 3: TFR cells express Bcl-6 and Blimp-1.
Figure 4: TFR cells derive from Foxp3+ precursors.
Figure 5: TFR cells regulate the size of the TFH cell population.
Figure 6: TFR cells restrict the outgrowth of non–antigen-specific clones in the germinal center.

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References

  1. Smith, K.G.C., Light, A., Nossal, G.J.V. & Tarlinton, D.M. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J. 16, 2996–3006 (1997).

    Article  CAS  Google Scholar 

  2. Guo, W. et al. Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity. J. Exp. Med. 207, 2225–2237 (2010).

    Article  CAS  Google Scholar 

  3. Vinuesa, C.G., Sanz, I. & Cook, M.C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845–857 (2009).

    Article  CAS  Google Scholar 

  4. Victora, G.D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010).

    Article  CAS  Google Scholar 

  5. Linterman, M.A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).

    Article  CAS  Google Scholar 

  6. Vinuesa, C.G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).

    Article  CAS  Google Scholar 

  7. Kim, H.J., Verbinnen, B., Tang, X., Lu, L. & Cantor, H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467, 328–332 (2010).

    Article  CAS  Google Scholar 

  8. Lim, H.W., Hillsamer, P., Banham, A.H. & Kim, C.H. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J. Immunol. 175, 4180–4183 (2005).

    Article  CAS  Google Scholar 

  9. Lim, H.W., Hillsamer, P. & Kim, C.H. Regulatory T cells can migrate to follicles upon T cell activation and suppress germinal center-Th cells and germinal center-Th cell-driven B cell responses. J. Clin. Invest. 114, 1640–1649 (2004).

    Article  CAS  Google Scholar 

  10. Fields, M.L. et al. CD4+ CD25+ regulatory T cells inhibit the maturation but not the initiation of an autoantibody response. J. Immunol. 175, 4255–4264 (2005).

    Article  CAS  Google Scholar 

  11. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  12. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  Google Scholar 

  13. Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+ CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  14. Bennett, C.L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    Article  CAS  Google Scholar 

  15. Wildin, R.S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

    Article  CAS  Google Scholar 

  16. Koch, M.A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).

    Article  CAS  Google Scholar 

  17. Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458, 351–356 (2009).

    Article  CAS  Google Scholar 

  18. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    Article  CAS  Google Scholar 

  19. Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

    Article  CAS  Google Scholar 

  20. Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004).

    Article  CAS  Google Scholar 

  21. Huehn, J. et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J. Exp. Med. 199, 303–313 (2004).

    Article  CAS  Google Scholar 

  22. Yoshida, K. et al. Bcl6 controls granzyme B expression in effector CD8+ T cells. Eur. J. Immunol. 36, 3146–3156 (2006).

    Article  CAS  Google Scholar 

  23. Cretney, E. et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 12, 304–311 (2011).

    Article  CAS  Google Scholar 

  24. Linterman, M.A. et al. Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30, 228–241 (2009).

    Article  CAS  Google Scholar 

  25. Linterman, M.A. & Vinuesa, C.G. Signals that influence T follicular helper cell differentiation and function. Semin. Immunopathol. 32, 183–196 (2010).

    Article  CAS  Google Scholar 

  26. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+ CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

    Article  CAS  Google Scholar 

  27. Tang, Q. et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+ CD25+ regulatory T cells. J. Immunol. 171, 3348–3352 (2003).

    Article  CAS  Google Scholar 

  28. Cannons, J.L. et al. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32, 253–265 (2010).

    Article  CAS  Google Scholar 

  29. Qi, H., Cannons, J.L., Klauschen, F., Schwartzberg, P.L. & Germain, R.N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008).

    Article  CAS  Google Scholar 

  30. Deenick, E.K. et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33, 241–253 (2010).

    Article  CAS  Google Scholar 

  31. Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).

    Article  CAS  Google Scholar 

  32. Nurieva, R.I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    Article  CAS  Google Scholar 

  33. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).

    Article  CAS  Google Scholar 

  34. Shaffer, A.L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002).

    Article  CAS  Google Scholar 

  35. Shaffer, A.L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000).

    Article  CAS  Google Scholar 

  36. Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  Google Scholar 

  37. Thornton, A.M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).

    Article  CAS  Google Scholar 

  38. Kim, J.M., Rasmussen, J.P. & Rudensky, A.Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

    Article  CAS  Google Scholar 

  39. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  Google Scholar 

  40. Rubtsov, Y.P. et al. Regulatory T cell–derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  Google Scholar 

  41. Rubtsov, Y.P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).

    Article  CAS  Google Scholar 

  42. Chan, T.D. et al. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J. Immunol. 183, 3139–3149 (2009).

    Article  CAS  Google Scholar 

  43. Willinger, T., Freeman, T., Hasegawa, H., McMichael, A.J. & Callan, M.F. Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets. J. Immunol. 175, 5895–5903 (2005).

    Article  CAS  Google Scholar 

  44. Martins, G.A. et al. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 (2006).

    Article  CAS  Google Scholar 

  45. Schmidt, E.M. et al. Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J. Immunol. 182, 274–282 (2009).

    Article  CAS  Google Scholar 

  46. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).

    Article  CAS  Google Scholar 

  47. Vinuesa, C.G., Tangye, S.G., Moser, B. & Mackay, C.R. Follicular B helper T cells in antibody responses and autoimmunity. Natl. Rev. Immunol. 5, 853–865 (2005).

    Article  CAS  Google Scholar 

  48. Hsu, H.C. et al. Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166–175 (2008).

    Article  CAS  Google Scholar 

  49. Gräbner, R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE−/− mice. J. Exp. Med. 206, 233–248 (2009).

    Article  Google Scholar 

  50. Wehner, J.R. et al. B cells and plasma cells in coronaries of chronically rejected cardiac transplants. Transplantation 89, 1141–1148 (2010).

    Article  Google Scholar 

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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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Author notes

  1. Kenneth G C Smith and Carola G Vinuesa: These authors contributed equally to this work.

Authors and Affiliations

  1. Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK

    Michelle A Linterman, Tim F Rayner, Devina P Divekar & Kenneth G C Smith

  2. John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia

    Michelle A Linterman, Sau K Lee, Monika Srivastava, Laura Beaton, Jennifer J Hogan & Carola G Vinuesa

  3. Vlaams Instituut voor Biotechnologie and Department of Experimental Medicine, Catholic University of Leuven, Leuven, Belgium

    Wim Pierson & Adrian Liston

  4. Department of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Axel Kallies

  5. Laboratory for Mucosal Immunity, RIKEN Research Center for Allergy and Immunology, Tsurumi, Yokohama, Japan

    Shimpei Kawamoto & Sidonia Fagarasan

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Contributions

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.

Corresponding authors

Correspondence to Adrian Liston, Kenneth G C Smith or Carola G Vinuesa.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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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