T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha

Nat Immunol. 2006 Nov;7(11):1166-73. doi: 10.1038/ni1394. Epub 2006 Oct 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Clonal Anergy / immunology*
  • Diacylglycerol Kinase / physiology*
  • Immunophenotyping
  • Isoenzymes / physiology
  • Mice
  • Mice, Transgenic
  • Th1 Cells / enzymology*
  • Th1 Cells / immunology*
  • ras Proteins / physiology*


  • Isoenzymes
  • Diacylglycerol Kinase
  • ras Proteins

Associated data

  • GEO/GSE5960