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 journalArticle

186 Citations (Scopus)

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

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Diacylglycerol Kinase
T-Lymphocytes
ras Guanine Nucleotide Exchange Factors
ras Proteins
Mitogen-Activated Protein Kinases
Interleukin-2
Cell Membrane

ASJC Scopus subject areas

  • Immunology

Cite this

Zha, Y., Marks, R., Ho, A. W., Peterson, A. C., Janardhan, S., Brown, I. E., ... Gajewski, T. F. (2006). T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α. Nature Immunology, 7(11), 1166-1173. https://doi.org/10.1038/ni1394

T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α. / Zha, Yuanyuan; Marks, Reinhard; Ho, Allen W.; Peterson, Amy C.; Janardhan, Sujit; Brown, Ian Elliott; Praveen, Kesavannair; Stang, Stacey; Stone, James C.; Gajewski, Thomas F.

In: Nature Immunology, Vol. 7, No. 11, 11.2006, p. 1166-1173.

Research output: Contribution to journalArticle

Zha, Y, Marks, R, Ho, AW, Peterson, AC, Janardhan, S, Brown, IE, Praveen, K, Stang, S, Stone, JC & Gajewski, TF 2006, 'T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α', Nature Immunology, vol. 7, no. 11, pp. 1166-1173. https://doi.org/10.1038/ni1394
Zha, Yuanyuan ; Marks, Reinhard ; Ho, Allen W. ; Peterson, Amy C. ; Janardhan, Sujit ; Brown, Ian Elliott ; Praveen, Kesavannair ; Stang, Stacey ; Stone, James C. ; Gajewski, Thomas F. / T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α. In: Nature Immunology. 2006 ; Vol. 7, No. 11. pp. 1166-1173.
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