HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dennehy, K. M. Articles by Lühder, F. Search for Related Content PubMed PubMed Citation Articles by Dennehy, K. M. Articles by Lühder, F.

Mitogenic CD28 Signals Require the Exchange Factor Vav1 to Enhance TCR Signaling at the SLP-76-Vav-Itk Signalosome¹

Kevin M. Dennehy^2,3,*, Fernando Elias^3,*, Shin-Young Na^*, Klaus-Dieter Fischer, Thomas Hünig^4,* and Fred Lühder^5,*

^* Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany; and Department of Physiological Chemistry, University of Ulm, Ulm, Germany

Almost all physiological T cell responses require costimulation—engagement of the clonotypic TCR with MHC/Ag and CD28 by its ligands CD80/86. Whether CD28 provides signals that are qualitatively unique or quantitatively amplify TCR signaling is poorly understood. In this study, we use superagonistic CD28 Abs, which induce T cell proliferation without TCR coligation, to determine how CD28 contributes to mitogenic responses. We show that mitogenic CD28 signals require but do not activate the proximal TCR components TCR and Zap-70 kinase. In cell lines lacking proximal TCR signaling, an early defect in the CD28 pathway is in phosphorylation of the adaptor molecule SLP-76, which we show is essential for recruitment of the exchange factor Vav leading to Ca²⁺ flux and IL-2 production. Point mutations in CD28 that result in diminished Vav phosphorylation also result in defective Ca²⁺ flux, IL-2 production, and Tec-kinase phosphorylation. Using Vav1-deficient mice, we further demonstrate the importance of Vav1 for efficient proliferation, IL-2 production, and Ca²⁺ flux. Our results indicate that CD28 signals feed into the TCR signaling pathway at the level of the SLP-76 signalosome.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Bundesministerium für Bildung und Forschung, project 01 KX 9820 E; Bayerisches Staatsministerium für Wissenschaft, Forschung und Bildung (Bayerischer Habilitationsförderpreis 2000) (to F.L.); Deutsche Forschungsgemeinschaft Graduate College 520 Immunomodulation (to F.E.); and Deutsche Forschungsgemeinschaft Grant Hu 295/7-1, 7-2 (to K.M.D.).

² Current address: Institute of Infectious Disease and Molecular Medicine, University of Cape Town 7925, South Africa.

³ K.M.D. and F.E. authors contributed equally to this work.

⁴ Address correspondence and reprint requests to Dr. Thomas Hünig, Institute of Virology and Immunobiology, University of Würzburg, Versbacher Straße 7, D-97078 Würzburg, Germany. E-mail address: huenig{at}vim.uni-wuerzburg.de

⁵ Current address: Institute for Multiple Sclerosis Research, University of Göttingen and Gemeinnützige Hertie-Stiftung, D-37073 Göttingen, Germany.

⁶ Abbreviations used in this paper: PLC, phospholipase C; LAT, linker for activation of T cell; WT, wild type; PKB, protein kinase B.

This article has been cited by other articles:

				F. Garcon, D. T. Patton, J. L. Emery, E. Hirsch, R. Rottapel, T. Sasaki, and K. Okkenhaug CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer Blood, February 1, 2008; 111(3): 1464 - 1471. [Abstract] [Full Text] [PDF]