IFN-gamma regulates Fas ligand expression in human CD4+ T lymphocytes and controls their anti-mycobacterial cytotoxic functions.
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.
Boselli
Daniela
D
Department of Medicine and Experimental Oncology, University of Turin, and Center for Experimental Research and Medical Studies, S. Giovanni Battista Hospital, Turin, Italy.
Losana
Giuliana
G
Bernabei
Paola
P
Bosisio
Daniela
D
Drysdale
Pamela
P
Kiessling
Rolf
R
Gaston
John S H
JS
Lammas
David
D
Casanova
Jean-Laurent
JL
Kumararatne
Dinakantha S
DS
Novelli
Francesco
F
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
D053222:Fas Ligand Protein; D007371:Interferon-gamma; D017471:Receptors, Interferon; D019014:fas Receptor; D000096743:Interferon gamma Receptor