Differential requirement of ZAP-70 for CD2-mediated activation pathways of mature human T cells.
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 zeta-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-alpha and IFN-gamma 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.
Meinl
E
E
Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, Germany. meinl@neuro.mpg.de
Lengenfelder
D
D
Blank
N
N
Pirzer
R
R
Barata
L
L
Hivroz
C
C
D018801:CD2 Antigens / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D018801:CD2 Antigens; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human