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


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.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Jandl, C.; Liu, S. M.; Canete, 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.;
Responsible Garvan Author A/Prof Cecile King
Publisher Name Nature Communications
Published Date 2017-03-01
Published Volume 8
Published Pages 14647
Status Published in-print
DOI 10.1038/ncomms14647
URL link to publisher's version
OpenAccess link to author's accepted manuscript version