title: T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha.
abstract: T cell anergy has been correlated with defective signaling by the GTPase Ras, but causal and mechanistic data linking defective Ras activity with T cell anergy are lacking. Here we used adenoviral transduction to genetically manipulate nonproliferating T cells and show that active Ras restored interleukin 2 production and mitogen-activated protein kinase signaling in T cells that were made anergic in vitro or in vivo. Diacylglycerol kinases (DGKs), which negatively regulate Ras activity, were upregulated in anergic T cells, and a DGK inhibitor restored interleukin 2 production in anergic T cells. Both anergy and DGK-alpha overexpression were associated with defective translocation of the Ras guanine nucleotide-exchange factor RasGRP1 to the plasma membrane. Our data support a causal function for excess DGK activity and defective Ras signaling in T cell anergy.
authors.affiliation: Department of Pathology, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zha
authors.forename: Reinhard
authors.initials: R
authors.lastname: Marks
authors.forename: Allen W
authors.initials: AW
authors.lastname: Ho
authors.forename: Amy C
authors.initials: AC
authors.lastname: Peterson
authors.forename: Sujit
authors.initials: S
authors.lastname: Janardhan
authors.forename: Ian
authors.initials: I
authors.lastname: Brown
authors.forename: Kesavannair
authors.initials: K
authors.lastname: Praveen
authors.forename: Stacey
authors.initials: S
authors.lastname: Stang
authors.forename: James C
authors.initials: JC
authors.lastname: Stone
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000818:Animals; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology*; D019852:Diacylglycerol Kinase / Q000502:physiology*; D016130:Immunophenotyping; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000201:enzymology* / Q000276:immunology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D007527:Isoenzymes; D019852:Diacylglycerol Kinase; D018631:ras Proteins