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Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells¹

Edgar Meinl^2,*,, Doris Lengenfelder^*, Norbert Blank, Rainer Pirzer^*, Luis Barata^§ and Claire Hivroz^¶

^* Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, Erlangen, Germany; Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany and Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University, Munich, Germany; Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany; ^§ Primary Immunodeficiencies Unit, Department of Allergy and Clinical Immunology, Coimbra Paediatric Hospital, Coimbra, Portugal; and ^¶ Institut National de la Santé et de la Recherche Médicale Unit 520, Institut Curie, Paris, France

This study addresses the role of the tyrosine kinase ZAP-70 in CD2-mediated T cell activation. Patients lacking ZAP-70 have few mature CD8⁺ T cells and high numbers of CD4⁺ T cells that are nonfunctional upon TCR triggering. Such a patient with a homozygous deletion in the zap-70 gene that resulted in the complete absence of ZAP-70 protein expression has been identified. Expression of the tyrosine kinases Lck, Fyn, and Syk was normal. The patient’s T cells were activated with two different pairs of mitogenic mAbs. CD2-induced phosphorylation of the -chain and influx of Ca²⁺ was defective in the ZAP-70-deficient T cells, whereas CD2-induced phosphorylation of several other proteins, including Syk, was not affected. CD2-induced proliferation as well as production of TNF- and IFN- was abrogated in ZAP-70-deficient T cells, whereas PMA plus ionomycin induced normal activation of these cells. Together, this study shows that CD2-activation triggers ZAP-70-dependent and -independent pathways. Deletion of ZAP-70 affected CD2- and CD3-mediated proliferation and cytokine production in a similar way, suggesting that one of the different CD2 pathways converges with a CD3 pathway at or upstream of the activation of ZAP-70.

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