IL-2-deficient mice were used to examine the role of endogenous IL-2 for supporting T cell proliferative responses during infection with lymphocytic choriomeningitis virus (LCMV). The studies showed that, although virus-specific CTL activity was induced in the absence of IL-2, the overall magnitude of the response was profoundly inhibited. Examination of proportions and numbers of CD8+ T cells demonstrated that the normal virus-induced expansion of these cells was virtually eliminated in spleens and dramatically decreased in lymph nodes from IL-2-negative mice. Absence of endogenous IL-2 also significantly inhibited virus-induced activated T cell production of IFN-gamma, as well as increases in frequencies and numbers of IFN-gamma-producing cells. Reductions in immune responses were accompanied by impaired viral clearance. Although T cell responses were dramatically reduced in IL-2-deficient, as compared with IL-2-containing mice, activation signals were being delivered in vivo because induced CTLs were sensitive to the cell cycle-specific toxin, hydroxyurea (HU), and CD8+ T cells had induced expression of the IL-2R alpha- and beta-chains. These studies demonstrated that, although low levels of T cell responses can be induced in the absence of IL-2, the factor plays a unique and critical role in supporting T cell proliferative responses in vivo and in optimizing induction of the biologic functions mediated by these cells. Furthermore, the results identify a role for IL-2 in promoting IFN-gamma production in vivo.