Our results indicate that interleukin (IL)-12 is an important costimulator of antigen-dependent proliferation of murine Th1 clones. In addition, we demonstrate that IL-10 inhibits splenic antigen-presenting cell (APC)-dependent proliferation of Th1 clones, at least in part, via down-regulation of APC-derived IL-12. Moreover, the failure of activated B cells to provide costimulation via IL-12 accounts for their inability to support optimal proliferative responses of Th1 clones. We also show that IL-12 regulates the ability of Th1 clones to respond to IL-4 and enhances their proliferation in response to IL-2, IL-7, or IL-15. In contrast, Th2 and Th0 clones appear refractory to the effects of IL-12, on antigen-dependent or growth factor-induced proliferation.