Mice that lack either CD40 (expressed on B cells) or CD40 ligand (expressed on activated T cells) are able neither to make IgG, IgA or IgE antibody responses, nor to generate germinal centres (the sites of formation of memory B cells). It has been assumed that these lesions were the result of an absence of signals to B cells through CD40. Here we show that the failure to signal T cells through CD40 ligand is an important contributory cause. Administration of soluble CD40 in vivo to CD40 knockout mice, restoring the missing signal through CD40 ligand initiates germinal centre formation. Furthermore, T cells primed in the absence of CD40 (in CD40 knockout mice) are unable to help normal B cells to class switch or to form germinal centres (GC). These results indicate that co-stimulation of T cells through CD40 ligand causes their differentiation into cells that help B cells to make mature antibody responses and to generate memory populations.