Upregulation of the kinase GCN2 correlates with protective immune responses induced by YF-17D, a live attenuated vaccine against yellow fever virus. In Science, Ravindran et al. investigate how activation of GCN2 enhances the immune response elicited by YF-17D. GCN2 is a sensor of the intracellular abundance of amino acids and induces an autophagic stress response in antigen-presenting dendritic cells (DCs) after infection with live-virus vaccines but not after vaccination with killed viruses. Mice deficient in GCN2 have fewer virus-specific CD4+ and CD8+ T cells, which suggests a defect in the priming of T cell responses. GCN2-deficient DCs have defective induction of autophagy and diminished cross-presentation of antigen. Similarly, DCs that lack expression of the autophagy proteins beclin-1, Atg5 or Atg7 are defective in cross-presentation. Curiously, priming of cells of the immune system is enhanced when both DCs and the dying YF-17D-infected cells express GCN2. Hence, infection with live virus depletes amino acid stores, which activates GCN2-dependent autophagy and enhances cross-presentation and the induction of protective adaptive immunity.

Science (5 December 2013) doi:10.1126/science.1246829