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J. Biol. Chem., Vol. 276, Issue 40, 36902-36908, October 5, 2001

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Herpesvirus saimiri Replaces ZAP-70 for CD3- and CD2-mediated T Cell Activation^*

Edgar Meinl^§¶, Tobias Derfuss, Rainer Pirzer, Norbert Blank^**, Doris Lengenfelder, Antoine Blancher, Françoise Le Deist^§§, Bernhard Fleckenstein, and Claire Hivroz^¶¶

From the  Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, D-82152 Martinsried, Germany, ^§ Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany,  Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany, ^** Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany,  Hôpital Purpan, 31059 Toulouse, France, ^§§ INSERM U429, Hôpital Necker, 75015 Paris, France and ^¶¶ INSERM U520, Institut Curie, 75248 Paris, France

The protein tyrosine kinase ZAP-70 plays a pivotal role involved in signal transduction through the T cell receptor and CD2. Defects in ZAP-70 result in severe combined immunodeficiency. We report that Herpesvirus saimiri, which does not code for a ZAP-70 homologue, can replace this tyrosine kinase. H. saimiri is an oncogenic virus that transforms human T cells to stable growth based on mutual CD2-mediated activation. Although CD2-mediated proliferation of ZAP-70-deficient uninfected T cells was absent, we could establish H. saimiri-transformed T cell lines from two unrelated patients presenting with ZAP-70 deficiencies. In these cell lines, CD2 and CD3 activation were restored in terms of [Ca²⁺]_i, MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of  remained defective. The transformed cells expressed very high levels of the ZAP-70-related kinase Syk. This increased expression was not observed in the primary T cells from the patients and was not due to the transformation by the virus because transformed cell lines established from control T cells did not present this particularity. In conclusion, wild type H. saimiri can restore CD2- and CD3-mediated activation in signaling-deficient human T cells. It extends our understanding of interactions between the oncogenic H. saimiri and the infected host cells.

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