The Journal of Experimental Medicine
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Published online 30 August 2004 doi:10.1084/jem.20040924
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 5, 681-687
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Brief Definitive Report

 Inhibition of T Cell Receptor Signal Transduction by Tyrosine Kinase–interacting Protein of Herpesvirus saimiri

Nam-Hyuk Cho, Pinghui Feng, Sun-Hwa Lee, Bok-Soo Lee, Xiaozhen Liang, Heesoon Chang, and Jae U. Jung

Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772

Address correspondence to Jae U. Jung, Tumor Virology Division, New England Primate Research Center, Harvard Medical School, P.O. Box 9102, 1 Pine Hill Dr., Southborough, MA 01772-9102. Tel.: (508) 624-8083; Fax: (508) 786-1416; email: jae_jung{at}hms.harvard.edu

T cells play a central role in orchestrating immunity against pathogens, particularly viruses. Thus, impairing T cell activation is an important strategy employed by viruses to escape host immune control. The tyrosine kinase–interacting protein (Tip) of the T lymphotropic Herpesvirus saimiri (HVS) is constitutively present in lipid rafts and interacts with cellular Lck tyrosine kinase and p80 endosomal protein. Here we demonstrate that, due to the sequestration of Lck by HVS Tip, T cell receptor (TCR) stimulation fails to activate ZAP70 tyrosine kinase and to initiate downstream signaling events. TCR {zeta} chains in Tip-expressing T cells were initially phosphorylated to recruit ZAP70 molecule upon TCR stimulation, but the recruited ZAP70 kinase was not subsequently phosphorylated, resulting in TCR complexes that were stably associated with inactive ZAP70 kinase. Consequently, Tip expression not only markedly inhibited TCR-mediated intracellular signal transduction but also blocked TCR engagement with major histocompatibility complexes on the antigen-presenting cells and immunological synapse formation. These results demonstrate that a lymphotropic herpesvirus has evolved a novel mechanism to deregulate T cell activation to disarm host immune surveillance. This process contributes to the establishment and maintenance of viral latency.

Key Words: Lck • ZAP70 • immunological synapse • tyrosine phosphorylation • CD3{zeta}

The online version of this article contains supplemental material.


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