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T cell memory depends on factors that regulate expansion and death of these cells after antigenic stimulation. Mice deficient in perforin and interferon-γ (IFN-γ) exhibited increased expansion, altered immunodominance, and decreased death of antigen-specific CD8⁺ T cells after infection with an attenuated strain ofListeria monocytogenes, which was cleared from these mice. Expansion of CD8⁺ T cells was controlled by perforin, whereas IFN-γ regulated immunodominance and the death phase. Thus, perforin and IFN-γ regulate distinct elements of CD8⁺ T cell homeostasis independently of their role as antimicrobial effector molecules.