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

Yuanyuan Zha, Reinhard Marks, Allen W. Ho, Amy C. Peterson, Sujit Janardhan, Ian Elliott Brown, Kesavannair Praveen, Stacey Stang, James C. Stone, Thomas F. Gajewski

Research output: Contribution to journalArticlepeer-review

202 Scopus citations

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-α 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.

Original languageEnglish (US)
Pages (from-to)1166-1173
Number of pages8
JournalNature Immunology
Volume7
Issue number11
DOIs
StatePublished - Nov 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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