Herpesvirus saimiri replaces ZAP-70 for CD3- and CD2-mediated T cell activation.
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 [Ca(2+)](i), MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of zeta 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.
Meinl
E
E
Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, D-82152 Martinsried, Germany. meinl@neuro.mpg.de
Derfuss
T
T
Pirzer
R
R
Blank
N
N
Lengenfelder
D
D
Blancher
A
A
Le Deist
F
F
Fleckenstein
B
B
Hivroz
C
C
D019898:Autocrine Communication; D018801:CD2 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D002455:Cell Division; D002472:Cell Transformation, Viral / Q000502:physiology*; D002478:Cells, Cultured; D004792:Enzyme Precursors / Q000378:metabolism; D005434:Flow Cytometry; D006567:Herpesvirus 2, Saimiriine / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology* / Q000821:virology; D051746:ZAP-70 Protein-Tyrosine Kinase
D018801:CD2 Antigens; D017252:CD3 Complex; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D020928:Mitogen-Activated Protein Kinases