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 language | English (US) |
|---|---|
| Pages (from-to) | 1166-1173 |
| Number of pages | 8 |
| Journal | Nature Immunology |
| Volume | 7 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2006 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α
AU - Zha, Yuanyuan
AU - Marks, Reinhard
AU - Ho, Allen W.
AU - Peterson, Amy C.
AU - Janardhan, Sujit
AU - Brown, Ian Elliott
AU - Praveen, Kesavannair
AU - Stang, Stacey
AU - Stone, James C.
AU - Gajewski, Thomas F.
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33750093594&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33750093594&partnerID=8YFLogxK
U2 - 10.1038/ni1394
DO - 10.1038/ni1394
M3 - Article
C2 - 17028589
AN - SCOPUS:33750093594
VL - 7
SP - 1166
EP - 1173
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
IS - 11
ER -