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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

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.

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Figure 1: Irgm1−/− CD4+ T cell populations fail to expand after TCR engagement.
Figure 2: Irgm1 is essential for the expansion of CD4+ T cell populations in the presence of IFN-γ.
Figure 3: Irgm1 promotes cell survival during pathogen-driven TH1 responses and prevents the IFN-γ-dependent mortality of mycobacteria-infected mice.
Figure 4: IFN-γ directly induces the death of Irgm1−/− CD4+ T cells.
Figure 5: Irgm1 prevents the IFN-γ-induced death of CD4+ T cells by regulating autophagy.

Change history

  • 05 October 2008

    In the version of this article initially published online, the genotype is missing in the first subheading of the Results section. The correct subheading is “Impaired expansion of activated Irgm1?/? CD4+ T cell populations.” The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank G. Taylor (Duke University) for Irgm1−/− mice backcrossed more than 12 times to C57BL/6 mice; S. White, C. Henry and C. Eigsti for technical assistance; J. Zhu and L. Yu for advice and discussions; K. Nagashima (Electron Microscope Facility, Image Analysis Laboratory, Science Applications International Corporation–National Cancer Institute, Frederick) for the electron microscopy studies; A. Cheever (Biomedical Research Institute) for assessing tissue fibrosis and pathology in S. mansoni infection experiments; R. Donnelly (Center for Biologics Evaluation and Research, Food and Drug Administration) for initial help in measuring STAT1 phosphorylation; and H. Young and D.L. Barber for critical reading of the manuscript. Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.

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C.G.F. designed the study, did research, analyzed results and wrote the manuscript; A.S. directed the study and wrote the manuscript; L.Z. and M.J.L. designed experiments, did research, analyzed results and contributed to the preparation of the manuscript; D.J., A.B., J.L.C., W.T.W., D.C. and P.L.S. did research and analyzed results; and S.H., and P.C. did research.

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Correspondence to Carl G Feng.

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Feng, C., Zheng, L., Jankovic, D. et al. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-γ-induced cell death. Nat Immunol 9, 1279–1287 (2008). https://doi.org/10.1038/ni.1653

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