IFN-γ is a pleiotropic cytokine that plays a key role in host resistance, yet when not properly regulated can become detrimental to the host. The interferon-inducible Immunity Related GTPase family M member 1 (Irgm1), previously characterized as an effector molecule required for macrophage microbicidal activity, has been shown recently to control IFN-γ-dependent cell survival and host resistance. Irgm1 regulates the expansion/survival of mature effector CD4⁺ T lymphocytes by protecting them from IFN-γ-induced autophagic cell death. Importantly, mice deficient in both IFN-γ and Irgm1 were rescued from the lymphocyte depletion and increased mortality that typically occurs in Irgm1^–/– animals following pathogen exposure. We propose that Irgm1 plays a major role in maintaining T lymphocyte homeostasis during host IFN-γ responses by protecting these cells from autophagy-dependent cell death.