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

Journal article

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.

Authors: Michel, F; Mangino, G; Attal-Bonnefoy, G; Tuosto, L; Alcover, A

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 165
• Issue: 7
• Pages: 3820-3829
• Publication date: 2000-10-01
• DOI: 10.4049/jimmunol.165.7.3820
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Signal Transduction; Pseudopodia; Antigens, CD28; Jurkat Cells; NFATC Transcription Factors; Proto-Oncogene Proteins c-vav; ZAP-70 Protein-Tyrosine Kinase; Transfection; Protein-Tyrosine Kinases; Phosphoproteins; Humans; Phosphorylation; Adaptor Proteins, Signal Transducing; Receptors, Antigen, T-Cell, alpha-beta; Cell Cycle Proteins; Nuclear Proteins; Transcription Factors; Proto-Oncogene Proteins; DNA-Binding Proteins; Adjuvants, Immunologic; src Homology Domains