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Originally published In Press as doi:10.1074/jbc.M908568199 on March 14, 2000

J. Biol. Chem., Vol. 275, Issue 21, 15832-15838, May 26, 2000
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Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk*

Nelly NorazDagger §, Klaus Schwarz, Marcos SteinbergDagger ||, Valérie DardalhonDagger , Cosette RebouissouDagger , Robert HipskindDagger , Wilhelm Friedrich**, Hans YsselDagger Dagger , Kevin Bacon§§¶¶, and Naomi TaylorDagger

From the Dagger  Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, 1919 Route de Mende, 34293 Montpellier, Cedex 5, France, the Departments of  Transfusion Medicine and ** Pediatrics, University of Ulm, D89081 Ulm, Germany, the Dagger Dagger  INSERM U454, 34295 Montpellier, France, and the §§ Department of Immunology, Neurocrine Biosciences Inc., San Diego, California 92121

ZAP-70-deficient patients present with nonfunctional CD4+ T cells in the periphery. We find that a subset of primary ZAP-70-deficient T cells, expressing high levels of the related protein-tyrosine kinase Syk, can proliferate in vitro. These cells (denoted herein as Sykhi/ZAP-70- T cells) provide a unique model in which the contribution of Syk to TCR-mediated responses can be explored in a nontransformed background. Importantly, CD3-induced responses, such as tyrosine phosphorylation of cellular substrates (LAT, SLP76, and PLC-gamma 1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Sykhi/ZAP-70- T cells. However, Sykhi/ZAP-70- T cells differ from control T cells with respect to the T cell antigen receptor (TCR)-mediated activation of the MAPK cascades: extracellular signal-regulated kinase activity and recruitment of the JNK and p38 stress-related MAPK pathways are diminished. This distinct phenotype of Sykhi/ZAP-70- T cells is associated with a profound decrease in CD3-mediated interleukin 2 secretion and proliferation relative to control T cells. Thus, ZAP-70 and Syk appear to play distinct roles in transducing a TCR-mediated signal.

* This work was supported by grants from the Association Française contre les Myopathies, Fondation de la Recherche Médicale (FRM), Association pour la Recherche sur le Cancer (ARC), Lique Nationale contre le Cancer, INSERM, and CNRS (to N. T.), JZKF.Ulm.CO.5 (to K. S.), and the FRM and ARC (to B. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a fellowship from the Association Française contre les Myopathies. To whom correspondence should be addressed. Tel.: 33-4-67-61-36-28; Fax: 33-4-67-04-02-31; E-mail: noraz@igm.cnrs-mop.fr

|| Supported by a fellowship from the Fundacion YPF.

¶¶ Present address: Bayer Yakuhin, Ltd., Kyoto 619-0216, Japan.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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