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      Stress kinase GCN2 controls the proliferative fitness and trafficking of cytotoxic T cells independent of environmental amino acid sensing

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          Summary

          GCN2 is one of four ‘stress kinases’ that block translation by phosphorylating eIF2α. GCN2 is thought to bind uncharged tRNAs to ‘sense’amino acids 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 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.

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          Journal
          101573691
          39703
          Cell Rep
          Cell Rep
          Cell reports
          2211-1247
          14 November 2016
          22 November 2016
          01 December 2016
          : 17
          : 9
          : 2247-2258
          Affiliations
          [1 ]Department of Infectious Diseases, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105
          [2 ]Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105
          Author notes
          [* ]Lead contact: peter.murray@ 123456stjude.org , 901-595-3219
          Article
          PMC5131879 PMC5131879 5131879 nihpa827661
          10.1016/j.celrep.2016.10.079
          5131879
          27880901
          09c9e7b7-44cd-4968-b873-0cbf6461f927
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