title: Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing.
abstract: GCN2 is one of four "stress kinases" that block translation by phosphorylating eIF2α. 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.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Lee-Ann
authors.initials: LA
authors.lastname: Van de Velde
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Xi-Zhi J
authors.initials: XJ
authors.lastname: Guo
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Lidija
authors.initials: L
authors.lastname: Barbaric
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Oguin
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: peter.murray@stjude.org.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes; D005786:Gene Expression Regulation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D013312:Stress, Physiological / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014364:Tryptophan / Q000494:pharmacology*
chemical_list: C515371:Ccr7 protein, mouse; D000939:Epitopes; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; D051742:Transcription Factor CHOP; D014364:Tryptophan; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: GCN2; T cell; amino acid; cytotoxic T cell; stress response; tryptophan