T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha.
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.
Zha
Yuanyuan
Y
Department of Pathology, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois 60637, USA.
Marks
Reinhard
R
Ho
Allen W
AW
Peterson
Amy C
AC
Janardhan
Sujit
S
Brown
Ian
I
Praveen
Kesavannair
K
Stang
Stacey
S
Stone
James C
JC
Gajewski
Thomas F
TF
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*
D007527:Isoenzymes; D019852:Diacylglycerol Kinase; D018631:ras Proteins