Two signaling pathways can lead to Fas ligand expression in CD8+ cytotoxic T lymphocyte clones.
As shown previously, a given cytotoxic T lymphocyte (CTL) clone (KB5.C20) could be induced to express the Fas ligand (FasL) by either T cell receptor (TCR) engagement or phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. In contrast, another CTL clone (BM3.3) has now been found to exert Fas-based cytotoxicity only after TCR engagement, but not after PMA/ionomycin stimulation. This suggested the existence of a PMA-insensitive, antigen-induced pathway leading to FasL expression. The inability of PMA to promote Fas-based cytotoxicity in BM3.3 cells was correlated with a defect in expression of the classical protein kinase C (PKC) isoforms alpha and beta I. In KB5.C20 cells depleted of PMA-sensitive PKC isoforms and thus no longer responsive to PMA, Fas-based cytotoxicity could still be induced via the TCR/CD3 pathway. On the other hand, a requirement for phosphatidylinositol-3 kinase (PI3K) selectively in this TCR/CD3-induced pathway was demonstrated by specific inhibition with wortmannin. These results suggest that FasL expression when induced via the TCR/CD3 involves PI3K, and when induced by PMA/ionomycin requires the expression of PMA-sensitive PKC isoforms absent in clone BM3.3. Additional data suggest that in neither case was NF-kappa B activation implicated in FasL expression.
Anel
A
A
Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, France.
Simon
A K
AK
Auphan
N
N
Buferne
M
M
Boyer
C
C
Golstein
P
P
Schmitt-Verhulst
A M
AM
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D015759:Ionomycin / Q000494:pharmacology; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000172:deficiency / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007527:Isoenzymes; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin