CD28 Signaling via VAV/SLP-76 Adaptors: Regulation of Cytokine Transcription Independent of TCR Ligation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2001-12, Vol.15 (6), p.921-933
• Main Authors: Raab, Monika, Pfister, Stefan, Rudd, Christopher E.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Adaptor Proteins, Signal Transducing; Amino Acid Motifs; Animals; B7-1 Antigen - genetics; B7-1 Antigen - immunology; Biopolymers; CD28 antigen; CD28 Antigens - physiology; Cell Cycle Proteins; Cell Membrane - metabolism; Cercopithecus aethiops; CHO Cells; COS Cells; Cricetinae; Cricetulus; DNA-Binding Proteins - metabolism; F-actin; Gene Expression Regulation - physiology; Humans; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Jurkat Cells - immunology; Ligands; Lymphocyte Activation - physiology; Macromolecular Substances; NFATC Transcription Factors; Nuclear Proteins; Phosphoproteins - chemistry; Phosphoproteins - physiology; Protein Binding; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-vav; rac1 GTP-Binding Protein - physiology; Receptors, Antigen, T-Cell - immunology; Recombinant Fusion Proteins - physiology; Signal Transduction - physiology; SLP-76 protein; T-Lymphocytes - immunology; Transcription Factors - metabolism; Transcription, Genetic - physiology; Vav protein
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/S1074-7613(01)00248-5

Since CD28 provides cosignals in T cell responses, a key question is whether the coreceptor operates exclusively via TCRζ/CD3 or also operates as an independent signaling unit. In this study, we show that CD28 can cooperate with VAV/SLP-76 adaptors to upregulate interleukin 2/4 transcription independently of TCR ligation. CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. CD28-VAV/SLP-76 also functions in nonlymphoid cells to promote nuclear entry of NFAT, indicating that these adaptors are the only lymphoid components needed for this pathway. Further downstream, CD28-VAV/SLP-76 synergizes with Rac1 and causes F-actin remodelling proximal to receptor. Autonomous CD28 signaling may account for the distinct nature of the second signal and in trans amplification of T cell responses.