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International Immunology, Vol. 15, No. 12, pp. 1441-1450, December 2003
© 2003 Japanese Society for Immunology

Differential implication of protein kinase C isoforms in cytotoxic T lymphocyte degranulation and TCR-induced Fas ligand expression

Julián Pardo1, Michel Buferne2, María-José Martínez-Lorenzo3, Javier Naval1, Anne-Marie Schmitt-Verhulst2, Claude Boyer2 and Alberto Anel1

1 Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain 2 Centre d‘Immunologie de Marseille–Luminy INSERM–CNRS–Université de la Méditerranée, 13288 Marseille, France 3 Servicio de Inmunología, Hospital Clínico Universitario ‘Lozano Blesa’, Universidad de Zaragoza, 50009 Zaragoza, Spain

Correspondence to: A. Anel; E-mail: anel{at}posta.unizar.es
Transmitting editor: J. Borst

CD8+ cytotoxic T lymphocyte (CTL) clones are able to exert both perforin- and Fas-dependent cytotoxicity. We show in the present work that phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 prevent TCR/CD3-induced functional Fas ligand (FasL) expression, but not perforin-dependent cytotoxicity. The specific inhibitor of classical protein kinase C (PKC) isoforms, Gö6976, completely inhibited perforin-dependent cytotoxicity and only affected slightly TCR/CD3-induced FasL expression, while the opposite was observed using rottlerin, an inhibitor with higher specificity for PKC{theta}. To address further the dependence of FasL expression on PI3K, a luciferase reporter controlled by the FasL promoter was used. Reporter gene induction by anti-CD3 mAb was abolished in cells transfected with dominant-negative PI3K (PI3K-DN) and increased in cells transfected with constitutively active PI3K (PI3K*). Transfection with constitutively active mutants (A/E) of PKC{epsilon}, and especially of PKC{theta}, improved anti-CD3 mAb-induced reporter expression and completely abolished inhibition by wortmannin, while transfection with dominant-negative (K/R) PKC{theta} prevented the induction of the reporter. Finally, transfection with PKC{alpha} A/E, but not with PKC{theta} A/E, cooperated with ionomycin to induce degranulation in the CTL line 1.3E6SN. Altogether, the results suggest that TCR/CD3-induced FasL gene transcription is controlled by PI3K and PKC{theta} activation, while this signaling pathway is not implicated in CTL degranulation, which is rather dependent on the activation of classical PKC isoforms.

Keywords: cellular activation, cytotoxicity, signal transduction, T lymphocyte


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