CTLA-4 has been proposed to negatively regulate immune responses, and mice deficient for CTLA-4 expression succumb to a lymphoproliferative disorder within a few weeks after birth. This study assessed the responsiveness of CTLA-4-deficient T cells expressing a class I-restricted TCR specific for lymphocytic choriomeningitis virus (LCMV). The kinetics of T cell proliferation were studied in vitro after stimulation of T cells with full and partial T cell agonists. No gross abnormalities in CTLA-4-deficient T cells could be detected. Using adoptive transfer experiments, T cell responses were also measured in vivo after infection with LCMV. Low dose infection with LCMV leads to strong expansion of specific T cells followed by a reduction in T cells that parallels the elimination of Ag. The kinetics of T cell expansion and elimination after low dose LCMV infection were not affected by the absence of CTLA-4. High dose infection of mice with LCMV leads to a transient expansion of T cells followed by T cell exhaustion, where all specific T cells are eliminated. T cell exhaustion also occurred in the absence of CTLA-4. Thus, surprisingly, the absence of CTLA-4 did not interfere with T cell activation, down-regulation of ongoing T cell responses after the elimination of Ag, or the exhaustion of T cell responses in the presence of excessive amounts of Ag.