Jandl, ChristophLiu, Sue M.Cañete, Pablo F.Warren, JoannaHughes, William E.Vogelzang, AlexisWebster, KylieCraig, Maria E.Uzel, GulbuDent, AlexanderStepensky, PolinaKeller, BärbelWarnatz, KlausSprent, JonathanKing, Cecile2020-02-062020-02-062017-03-17Jandl, C., Liu, S. M., Cañete, P. F., Warren, J., Hughes, W. E., Vogelzang, A., … 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. doi:10.1038/ncomms14647https://hdl.handle.net/1805/22007T 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.en-USAttribution 4.0 InternationalImmunity, HumoralImmunologic Deficiency SyndromesInterleukin-21 Receptor alpha SubunitProto-Oncogene Proteins c-bcl-6T-Lymphocytes, RegulatoryArticle