The immunity-related GTPase family M, member 1 (IRGM1) protects T cells from the toxic effects of IFN while promoting its antimicrobial effects.
To contribute to resistance against many microbial infections, activated T cells and natural killer cells produce interferon- (IFN). Although high levels of IFN are required for its antimicrobial activity, they are toxic to nearby cells. So, how do T cells survive and accumulate in the presence of this cytokine? Feng et al. now show that immunity-related GTPase family M, member 1 (IRGM1) protects T cells from the toxic effects of IFN while promoting its antimicrobial effects.
Compared with wild-type mice, Irgm1-/- mice are known to be more susceptible to infection with various intracellular pathogens, and this susceptibility is associated with profound lymphopenia. The authors reasoned that this might be due, in part, to impaired survival of effector T cells. Indeed, in vitro analysis revealed that Irgm1-/- CD4+ T cells had poor proliferative capacity and reduced survival following T-cell receptor stimulation. These defects were shown to be IFN dependent, as T cells from mice lacking both IRGM1 and IFN had normal proliferative capacity and survival. In contrast to Irgm1-/- mice, the Irgm1-/- Ifng-/- mice survived an otherwise lethal infection with Mycobacterium avium and did not develop lymphopenia, which indicates that IRGM1 might be required to protect lymphocytes from inhibition mediated by IFN.
Further investigation of the mechanism of IFN-mediated suppression of Irgm1-/- T-cell numbers indicated that increased cell death, rather than decreased cell division, was responsible. Interestingly, the mechanism of cell death was found to involve autophagy: IFN-exposed Irgm1-/- T cells contained more membrane-bound vacuoles that closely resembled autophagosomes than Irgm1-/- Ifng-/- T cells. In addition, IFN-induced death of Irgm1-/- T cells could be prevented by treatment with inhibitors of phosphoinositide 3-kinase or by knockdown of expression of beclin-1, two proteins that are known to be involved in autophagy.
So, given that IRGM1 expression is induced by IFN, these data suggest that IRGM1 provides a positive-feedback mechanism that protects activated CD4+ T cells from IFN-dependent autophagic cell death to ensure a beneficial outcome of the IFN response.
Lucy Bird
References
Feng, C. G. et al. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon--induced cell death. Nature Immunol.9, 1279–1287 (2008) | Article | PubMed |
while promoting its antimicrobial effects.
