MECHANISMS OF SIGNAL TRANSDUCTION
Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk*

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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-γ1), 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.

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Published, JBC Papers in Press, March 14, 2000, DOI 10.1074/jbc.M908568199

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N. Taylor, unpublished observations.

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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 Fundacion YPF.

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