1. IFN-gamma regulates Fas ligand expression in human CD4+ T lymphocytes and controls their anti-mycobacterial cytotoxic functions
- Author
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Jean-Laurent Casanova, Francesco Novelli, Daniela Bosisio, Rolf Kiessling, Dinakantha S. Kumararatne, J. S. H. Gaston, Giuliana Losana, David A. Lammas, Paola Bernabei, Pamela Drysdale, and Daniela Boselli
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Fas Ligand Protein ,medicine.medical_treatment ,T cell ,Immunology ,Apoptosis ,Biology ,Major histocompatibility complex ,Jurkat cells ,Fas ligand ,Mycobacterium ,Interferon-gamma ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,fas Receptor ,Receptors, Interferon ,Mycobacterium Infections ,Microscopy, Confocal ,Reverse Transcriptase Polymerase Chain Reaction ,hemic and immune systems ,Flow Cytometry ,Molecular biology ,Cytokine ,medicine.anatomical_structure ,biology.protein ,CD8 - 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.
- Published
- 2007