title: GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.
abstract: Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.
authors.affiliation: Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912, USA. dmunn@mail.mcg.edu
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Madhav D
authors.initials: MD
authors.lastname: Sharma
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D017635:Clonal Anergy; D003713:Dendritic Cells / Q000276:immunology; D004789:Enzyme Activation; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014364:Tryptophan / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases