Title: The oncogene product Vav is a crucial regulator of primary cytotoxic T cell responses but has no apparent role in CD28-mediated co-stimulation
Abstract: European Journal of ImmunologyVolume 29, Issue 5 p. 1709-1718 ArticleFree Access The oncogene product Vav is a crucial regulator of primary cytotoxic T cell responses but has no apparent role in CD28-mediated co-stimulation Josef M. Penninger, Corresponding Author Josef M. Penninger [email protected] Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaAmgen Institute, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada Fax: +1-4162042278Search for more papers by this authorKlaus D. Fischer, Klaus D. Fischer Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, GermanySearch for more papers by this authorTakehiko Sasaki, Takehiko Sasaki Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaSearch for more papers by this authorIvona Kozieradzki, Ivona Kozieradzki Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaSearch for more papers by this authorJennifer Le, Jennifer Le Amgen Institute Toronto, CanadaSearch for more papers by this authorKerry Tedford, Kerry Tedford Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, GermanySearch for more papers by this authorKurt Bachmaier, Kurt Bachmaier Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaSearch for more papers by this authorPamela S. Ohashi, Pamela S. Ohashi Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, GermanySearch for more papers by this authorMartin F. Bachmann, Martin F. Bachmann Basel Institute for Immunology, Basel, SwitzerlandSearch for more papers by this author Josef M. Penninger, Corresponding Author Josef M. Penninger [email protected] Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaAmgen Institute, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada Fax: +1-4162042278Search for more papers by this authorKlaus D. Fischer, Klaus D. Fischer Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, GermanySearch for more papers by this authorTakehiko Sasaki, Takehiko Sasaki Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaSearch for more papers by this authorIvona Kozieradzki, Ivona Kozieradzki Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaSearch for more papers by this authorJennifer Le, Jennifer Le Amgen Institute Toronto, CanadaSearch for more papers by this authorKerry Tedford, Kerry Tedford Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, GermanySearch for more papers by this authorKurt Bachmaier, Kurt Bachmaier Amgen Institute Toronto, Canada Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, CanadaSearch for more papers by this authorPamela S. Ohashi, Pamela S. Ohashi Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, GermanySearch for more papers by this authorMartin F. Bachmann, Martin F. Bachmann Basel Institute for Immunology, Basel, SwitzerlandSearch for more papers by this author First published: 28 March 2006 https://doi.org/10.1002/(SICI)1521-4141(199905)29:05<1709::AID-IMMU1709>3.0.CO;2-OCitations: 31AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract The guanine nucleotide-exchange factor Vav is a regulator of antigen-mediated cytoskeletal reorganization required for receptor clustering, proliferation and thymic selection. Moreover, Vav has been identified as a major substrate in the CD28 signal transduction pathway and overexpression of Vav enhances TCR-mediated IL-2 secretion in T cells. Here we show that CD3- plus CD28-mediated proliferation and IL-2 production were reduced in vav gene-deficient T cells. However, Vav had no apparent role in phorbol 12-myristate 13-acetate- plus CD28-mediated proliferation and IL-2 production, suggesting that Vav acts downstream of the TCR/CD3 complex. In vivo, Vav expression was crucial to generate primary vesicular stomatitis virus (VSV)-specific cytotoxic T cell responses. In contrast, vav − / − mice exhibited a reduced but significant footpad swelling after lymphocytic choriomeningitis virus (LCMV) infections and mounted a measurable primary cytotoxic T cell response to LCMV. Upon in vitro restimulation, cytotoxic T cell responses of both VSV- and LCMV-infected mice reached near normal levels. Our data provide the first genetic evidence that Vav is an important effector molecule that relays antigen receptor signaling to IL-2 production and activation of cytotoxic T cells. Reference 1 Collins, T. L., Deckert, M. and Altman, A., Views On Vav. Immunol. Today 1997. 18: 221–225. 2 Margolis, B., Hu, P., Katzav, S., Li, W., Oliver, J. M., Ullrich, A., Weiss, A. and Schlessinger, J., Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. Nature 1992. 356: 71–74. 3 Bustelo, X. R., Led better, J. A. and Barbacid, M., Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates. 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