Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing

GCN2 is one of four stress kinases that block translation by phosphorylating eIF2a. GCN2 is thought to bind uncharged tRNAs to sense amino acid availability. In mammals, myeloid cells expressing indoleamine dioxygenases locally deplete tryptophan, which is detected by GCN2 in T cells to cause proliferative arrest. GCN2-deficient T cells were reported to ectopically enter the cell cycle when tryptophan was limiting. Using GCN2-deficient strains crossed to T cell receptor (TCR) transgenic backgrounds, we found GCN2 is essential for induction of stress target genes such as CHOP. However, GCN2-deficient CD8(+) T cells fail to proliferate in limiting tryptophan, arginine, leucine, lysine, or asparagine, the opposite of what previous studies concluded. In vitro and in vivo proliferation experiments show that GCN2-deficient CD8(+) T cells have T cell-intrinsic proliferative and trafficking defects not observed in CD4(+) T cells. Thus, GCN2 is required for normal cytotoxic T cell function.