title: The Interaction of CD154 with the α5β1 Integrin Inhibits Fas-Induced T Cell Death.
abstract: CD154, a critical regulator of the immune response, is usually associated with chronic inflammatory, autoimmune diseases as well as malignant disorders. In addition to its classical receptor CD40, CD154 is capable of binding other receptors, members of the integrin family, the αIIbβ3, αMβ2 and α5β1. Given the role attributed to integrins and particularly the β1 integrins in inhibiting apoptotic events in normal as well as malignant T cells, we were highly interested in investigating the role of the CD154/α5β1 interaction in promoting survival of malignant T cells contributing as such to tumor development and/or propagation. To support our hypothesis, we first show that soluble CD154 binds to the T-cell acute lymphoblastic leukemia cell line, Jurkat E6.1 in a α5β1-dependent manner. Binding of soluble CD154 to α5β1 integrin of Jurkat cells leads to the activation of key survival proteins, including the p38 and ERK1/2 mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinase (PI-3K), and Akt. Interestingly, soluble CD154 significantly inhibits Fas-mediated apoptosis in T cell leukemia-lymphoma cell lines, Jurkat E6.1 and HUT78 cells, an important hallmark of T cell survival during malignancy progression. These anti-apoptotic effects were mainly mediated by the activation of the PI-3K/Akt pathway but also involved the p38 and the ERK1/2 MAPKs cascades. Our data also demonstrated that the CD154-triggered inhibition of the Fas-mediated cell death response was dependent on a suppression of caspase-8 cleavage, but independent of de novo protein synthesis or alterations in Fas expression on cell surface. Together, our results highlight the impact of the CD154/α5β1 interaction in T cell function/survival and identify novel targets for the treatment of malignant disorders, particularly of T cell origin.
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
authors.forename: Meriem
authors.initials: M
authors.lastname: Bachsais
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
authors.forename: Nadim
authors.initials: N
authors.lastname: Naddaf
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yacoub
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Salti
authors.affiliation: Department of Pathology, 11-5076, Faculty of Medicine, St Joseph University, Beirut, Lebanon.
authors.forename: Nada
authors.initials: N
authors.lastname: Alaaeddine
authors.affiliation: Centre de recherche en immunologie et rhumatologie, CHUL, 2705, Boul Laurier, QC, Canada.
authors.forename: Fawzi
authors.initials: F
authors.lastname: Aoudjit
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Tour Viger, Room 10-482, Montréal, QC, Canada.
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
mesh_terms: D023201:CD40 Ligand / Q000276:immunology*; D053181:Caspase 8 / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019030:Receptors, Vitronectin / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
chemical_list: C491901:FAS protein, human; D019030:Receptors, Vitronectin; D019014:fas Receptor; C094340:integrin alphavbeta1; D023201:CD40 Ligand; D048049:Extracellular Signal-Regulated MAP Kinases; C505530:CASP8 protein, human; D053181:Caspase 8