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, Cecile King

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish (US)
Article number14647
JournalNature communications
Volume8
DOIs
StatePublished - Mar 17 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Jandl, C., Liu, S. M., Cañete, P. F., Warren, J., Hughes, W. E., Vogelzang, A., Webster, K., Craig, M. E., Uzel, G., Dent, A., Stepensky, P., Keller, B., Warnatz, K., Sprent, J., & King, C. (2017). IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2. Nature communications, 8, [14647]. https://doi.org/10.1038/ncomms14647