T follicular helper (Tfh) cells play a fundamental role in the germinal centre (GC) reaction to T-dependent antigen, and are essential for the production of class-switched, high-affinity antibody. The influence of cytokine growth factors, including the cytokines interleukin-21 (IL-21), IL-6 and IL-2 on the development and survival of Tfh cells has been well documented. In recent years growing interest has emerged for a FoxP3-expessing T follicular regulatory (Tfr) subset which influences the GC response by suppressing Tfh cell function. As IL-21 has been shown to control regulatory T cell (Treg) function and Tfr cells derive from thymic nTregs we became interested in its role on this subset. To study the underlying mechanism of IL-21s effects on Tfh and Tfr cells, the humoral immune response to T-dependent antigen was analysed in Il21rSTAT mice harbouring a point mutation the cytoplasmic tail of the IL21-receptor alpha-chain. In response to IL-21, Il21rSTAT mice exhibit diminished STAT1 phosphoylation whereas STAT3-signalling appears intact. This relatively minor effect on signalling resulted in increased numbers of Tregs and Tfr cells. By contrast Tfh cell numbers and both GC B cell and IgG1+ class-switched B cell numbers were significantly decreased. Thus IL-21-mediated STAT1 activation favors the development of the humoral immune response.