Inhibition of protein tyrosine phosphorylation prevents T-cell-mediated cytotoxicity.
Several lines of evidence point to a central role for protein tyrosine kinases (PTKs) in the signal transduction cascade initiated by T-cell receptor (TCR) engagement. In cytotoxic T lymphocytes (CTL), TCR crosslinking leads to activation of the lytic process which includes conjugate formation, lethal hit delivery, and events leading to target cell death. We studied the role of PTKs in antigen-specific cytotoxicity exerted by both in vivo activated and in vitro maintained CTL. We found that the PTK inhibitors herbimycin A and genistein blocked T-cell-mediated lysis in a dose-dependent manner. Lack of cytotoxic function was not due to abrogation of conjugate formation, but was associated with inhibition of both granule exocytosis and phosphatidylinositides turnover, thus indicating that PTK activity is an obligatory event for the activation of antigen-specific CTL effector function.
Rosato
A
A
Institute of Oncology, University of Padua, Italy.
Zambon
A
A
Mandruzzato
S
S
Bronte
V
V
Macino
B
B
Calderazzo
F
F
Collavo
D
D
Zanovello
P
P
D000818:Animals; D016227:Benzoquinones; D016923:Cell Death / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D004247:DNA / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005434:Flow Cytometry; D019833:Genistein; D007295:Inositol Phosphates / Q000096:biosynthesis; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D051379:Mice; D008811:Mice, Inbred DBA; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D007295:Inositol Phosphates; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D004247:DNA; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D004950:Esterases