Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis.
Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91(phox) to characterize the molecular link to activated T cell apoptosis, we show that gp91(phox)-deficient T (T(-/-)) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase-dependent Bax activation and apoptosis. Activated T(-/-) cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.
Purushothaman
Divya
D
National Centre for Biological Sciences, Bellary Road, Bangalore 560065, Karnataka, India.
Sarin
Apurva
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D004789:Enzyme Activation; D006706:Homeostasis; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D054400:Receptors, CCR7; D051028:bcl-2-Associated X Protein; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases