Dimeric or aggregated IgD causes augmentation of primary and secondary Ab responses in mice when injected a few days before or together with the primary dose of Ag. This effect is mediated by Th cells and seems to be linked to the up-regulation of receptors for IgD on CD4+ T cells. IgD-R cross-linking is needed for receptor up-regulation. Here we show that addition of monomeric IgD to dimeric or aggregated IgD blocks IgD-R up-regulation on T cells in vitro and in vivo, as well as their immunoaugmenting effect in vivo. More importantly, monomeric IgD injected 6 to 24 h before a primary Ag injection also inhibits 1) the up-regulation of IgD-R on T cells induced by Ag injection alone, and 2) the generation of IgG memory, as shown in the response to a second dose of Ag injected on day 10. These results suggest that IgD-R on T cells contribute to the T-B cell interaction involved in the priming for a secondary response. The augmenting effect of oligomeric IgD and the inhibiting effect of monomeric IgD on secondary Ab responses are not observed in IgD-/- (IgD-deficient) mice, although injection of oligomeric IgD leads to IgD-R up-regulation on T cells in these mice. These results indicate that IgD presented in the form of immune complexes, most likely on the surface of B cells, is a prerequisite for the immunoaugmenting effects exerted by IgD-R+ T cells. Thus, IgD is the only physiologic ligand for IgD-R on T cells.