CD28 utilizes Vav-1 to enhance TCR-proximal signaling and NF-AT activation

被引:75
作者
Michel, F
Mangino, G
Attal-Bonnefoy, G
Tuosto, L
Alcover, A
Roumier, A
Olive, D
Acuto, O
机构
[1] Inst Pasteur, Dept Immunol, Mol Immunol Unit, F-75724 Paris 15, France
[2] Inst Pasteur, Biol Cellular Interact Unit, F-75724 Paris 15, France
[3] Inst Natl Sante & Rech Med, Unit 119, Marseille, France
关键词
D O I
10.4049/jimmunol.165.7.3820
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The mechanism through which CD28 costimulation potentiates TCR-driven gene expression is still not clearly defined. Vav-1, an exchange factor for Rho GTPases thought to regulate, mainly through Rac-1, various signaling components leading to cytokine gene expression, is tyrosine phosphorylated upon CD28 engagement. Here, we provide evidence for a key role of Vav-1 in CD28-mediated signaling. Overexpression of Vav-1 in Jurkat cells in combination with CD28 ligation strongly reduced the concentration of staphylococcus enterotoxin E/MHC required for TCR-induced NF-AT activation. Surprisingly, upon Vav-1 overexpression CD28 ligation sufficed to activate NF-AT in the absence of TCR engagement. This effect was not mediated by overexpression of ZAP-70 nor of SLP-76 but necessitated the intracellular tail of CD28, the intactness of the TCR-proximal signaling cascade, the Src-homology domain 2 (SH2) domain of Vav-1, and SLP-76 phosphorylation, an event which was favored by Vav-1 itself. Cells overexpressing Vav-1 formed lamellipodia and microspikes reminiscent of Rac-1 and Cdc42 activation, respectively, for which the SH2 domain of Vav-1 was dispensable. Together, these data suggest that CD28 engagement activates Vav-1 to boost TCR signals through a synergistic cooperation between Vav-1 and SLP-76 and probably via cortical actin changes to facilitate the organization of a signaling zone.
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页码:3820 / 3829
页数:10
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