title: CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation.
abstract: Since CD28 provides cosignals in T cell responses, a key question is whether the coreceptor operates exclusively via TCRzeta/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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Raab
authors.forename: S
authors.initials: S
authors.lastname: Pfister
authors.forename: C E
authors.initials: CE
authors.lastname: Rudd
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D001704:Biopolymers; D018106:CD28 Antigens / Q000502:physiology*; D016466:CHO Cells; D019556:COS Cells; D018797:Cell Cycle Proteins; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000502:physiology*; D046911:Macromolecular Substances; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018122:B7-1 Antigen; D001704:Biopolymers; D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008024:Ligands; D046911:Macromolecular Substances; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C092947:SLP-76 signal Transducing adaptor proteins; D014157:Transcription Factors; C496618:VAV1 protein, human; D015847:Interleukin-4; D020830:rac1 GTP-Binding Protein