Nature Immunology
- 7, 1166 - 1173 (2006)
Published online: 8 October 2006; Corrected online: 03 November 2006 | doi:10.1038/ni1394
There is an Erratum (December 2006) associated with this Article.
T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase- Yuanyuan Zha1, 4, Reinhard Marks1, 3, 4, Allen W Ho1, 4, Amy C Peterson1, Sujit Janardhan1, Ian Brown1, Kesavannair Praveen1, Stacey Stang2, James C Stone2 & Thomas F Gajewski11
Departments of Pathology and Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois 60637 USA. 2
Department of Biochemistry, The University of Alberta, Edmonton, Alberta T6G2E1, Canada. 3
Present address: Department of Hematology and Oncology, University Hospital Freiberg, 79106 Freiberg, Germany. 4
These authors contributed equally to this work.
Correspondence should be addressed to Thomas F Gajewski tgajewsk@medicine.bsd.uchicago.edu 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- 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.
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