Inhibition of T cell receptor signal transduction by tyrosine kinase-interacting protein of Herpesvirus saimiri.
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.
Cho
Nam-Hyuk
NH
Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
Feng
Pinghui
P
Lee
Sun-Hwa
SH
Lee
Bok-Soo
BS
Liang
Xiaozhen
X
Chang
Heesoon
H
Jung
Jae U
JU
D000938:Antigen-Presenting Cells / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017252:CD3 Complex / Q000378:metabolism; D006567:Herpesvirus 2, Saimiriine / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D037181:Lectins, C-Type; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014443:Tyrosine / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D037181:Lectins, C-Type; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D014764:Viral Proteins; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C092384:tyrosine kinase interacting protein, Saimiriine herpesvirus 2; C497261:ZAP70 protein, human