The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-γ-induced cell death

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Abstract
Interferon-γ (IFN-γ) is toxic to cells, yet IFN-γ-producing cells survive. Feng and colleagues show that expression of the GTPase Irgm1 in these cells confers protection against IFN-γ toxicity. Mice deficient in the interferon-γ (IFN-γ)-inducible, immunity-related GTPase Irgm1 have defective host resistance to a variety of intracellular pathogens. This greater susceptibility to infection is associated with impaired IFN-γ-dependent macrophage microbicidal activity in vitro. Here we show that Irgm1 also regulated the survival of mature effector CD4+ T lymphocytes by protecting them from IFN-γ-induced autophagic cell death. Mice deficient in both IFN-γ and Irgm1 were 'rescued' from the lymphocyte depletion and greater mortality that occurs in mice singly deficient in Irgm1 after mycobacterial infection. Our studies identify a feedback mechanism in the T helper type 1 response that limits the detrimental effects of IFN-γ on effector T lymphocyte survival while promoting the antimicrobial functions of IFN-γ.