title: IFN-gamma regulates Fas ligand expression in human CD4+ T lymphocytes and controls their anti-mycobacterial cytotoxic functions.
abstract: Fas and Fas Ligand (FasL) expression, activation-induced cell death (AICD) and mycobacterial antigen-specific cytotoxicity of peripheral T cells from patients with complete inherited IFN-gamma receptor 1 binding chain deficiency (IFN-gammaR1-/-) were investigated. Fas was equally expressed in both normal and deficient T lymphoblasts and they underwent apoptosis when stimulated with agonist anti-Fas mAb. By contrast, T lymphoblasts and CD4+ T cell clones (TCC) from deficient patients displayed a reduced surface FasL expression and resistance to AICD. CD8+ TCC from healthy and deficient patients displayed similar high level of FasL and susceptibility to AICD. In Jurkat CD4+ T cells competent to transduce IFN-gamma signaling, IFN-gamma induced surface FasL export and their Fas-dependent apoptosis. Effector T cells generated from a patient with a dominant negative mutation of IFN-gammaR1 (IFN-gammaR1DN) following stimulation with mycobacterial antigens were unable to kill MHC class II-matched, mycobacterial antigen-pulsed macrophages. Normal Fas expression in T cells and FasL in CD8+ cells may account for the absence of autoimmune disorders in these patients. Conversely, defective FasL expression on IFN-gammaR1DN CD4+ T cells impairs their cytotoxic functions and highlights a novel role for IFN-gamma signaling in the control of mycobacterial infection in humans.
authors.affiliation: Department of Medicine and Experimental Oncology, University of Turin, and Center for Experimental Research and Medical Studies, S. Giovanni Battista Hospital, Turin, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Boselli
authors.forename: Giuliana
authors.initials: G
authors.lastname: Losana
authors.forename: Paola
authors.initials: P
authors.lastname: Bernabei
authors.forename: Daniela
authors.initials: D
authors.lastname: Bosisio
authors.forename: Pamela
authors.initials: P
authors.lastname: Drysdale
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: John S H
authors.initials: JS
authors.lastname: Gaston
authors.forename: David
authors.initials: D
authors.lastname: Lammas
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Dinakantha S
authors.initials: DS
authors.lastname: Kumararatne
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000096:biosynthesis*; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D009161:Mycobacterium / Q000276:immunology; D009164:Mycobacterium Infections / Q000276:immunology*; D017471:Receptors, Interferon / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
chemical_list: D053222:Fas Ligand Protein; D007371:Interferon-gamma; D017471:Receptors, Interferon; D019014:fas Receptor; D000096743:Interferon gamma Receptor