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

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, Klaus Warnatz, Jonathan Sprent and Cecile King ()
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Christoph Jandl: Garvan Institute of Medical Research
Sue M. Liu: Garvan Institute of Medical Research
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
Maria E. Craig: Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney
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
Cecile King: Garvan Institute of Medical Research

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14647

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