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IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Author

Listed:
  • Christoph Jandl

    (Garvan Institute of Medical Research
    St Vincent’s Clinical School, University of NSW)

  • Sue M. Liu

    (Garvan Institute of Medical Research
    St Vincent’s Clinical School, University of NSW)

  • Pablo F. Cañete

    (John Curtin School of Medical Research, The Australian National University)

  • Joanna Warren

    (Garvan Institute of Medical Research)

  • William E. Hughes

    (Garvan Institute of Medical Research)

  • Alexis Vogelzang

    (Garvan Institute of Medical Research)

  • Kylie Webster

    (Garvan Institute of Medical Research
    St Vincent’s Clinical School, University of NSW)

  • Maria E. Craig

    (Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney
    School of Women’s and Children’s Health, University of New South Wales)

  • Gulbu Uzel

    (Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Alexander Dent

    (Indiana University School of Medicine)

  • Polina Stepensky

    (Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Kiryat Hadassah)

  • Bärbel Keller

    (Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg)

  • Klaus Warnatz

    (Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg)

  • Jonathan Sprent

    (Garvan Institute of Medical Research
    St Vincent’s Clinical School, University of NSW)

  • Cecile King

    (Garvan Institute of Medical Research
    St Vincent’s Clinical School, University of NSW)

Abstract

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

Suggested Citation

  • Christoph Jandl & Sue M. Liu & Pablo F. Cañete & Joanna Warren & William E. Hughes & Alexis Vogelzang & Kylie Webster & Maria E. Craig & Gulbu Uzel & Alexander Dent & Polina Stepensky & Bärbel Keller , 2017. "IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14647
    DOI: 10.1038/ncomms14647
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    Cited by:

    1. Dimitra Zotos & Isaak Quast & Connie S. N. Li-Wai-Suen & Craig I. McKenzie & Marcus J. Robinson & Andrey Kan & Gordon K. Smyth & Philip D. Hodgkin & David M. Tarlinton, 2021. "The concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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