title: Apoptosis-inducing factor regulates death in peripheral T cells.
abstract: Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein with multiple roles in apoptosis as well as in cellular respiration and redox regulation. The harlequin (Hq) mouse strain carries an aif locus modification causing reduced Aif expression. We demonstrate that activated CD4(+) and CD8(+) peripheral T cells from Hq mice show resistance to neglect-induced death (NID) triggered by growth factor withdrawal, but not to death induced by multiple agents that trigger DNA damage. Aif translocates to the nucleus in cells undergoing NID, and, in Hq T cell blasts, resistance to NID is associated with reduced cytosolic release of mitochondrial cytochrome c, implicating Aif in this event. In contrast, Hq T cell blasts express higher levels of CD95L, demonstrating increased susceptibility to activation-induced cell death (AICD) and apoptosis triggered by hydrogen peroxide. Superoxide scavenging protects from AICD in wild-type, but not Hq, T cell blasts, suggesting that Aif plays a crucial superoxide-scavenging role to regulate T cell AICD. Finally, the altered pattern of death susceptibility is reproduced by siRNA-mediated reduction of Aif expression in normal T cells. Thus, Aif serves nonredundant roles, both proapoptotic and antiapoptotic, in activated peripheral T cells.
authors.affiliation: National Institute of Immunology, New Delhi, India.
authors.forename: Smita
authors.initials: S
authors.lastname: Srivastava
authors.forename: Hridesh
authors.initials: H
authors.lastname: Banerjee
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chaudhry
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.forename: Apurva
authors.initials: A
authors.lastname: Sarin
authors.forename: Anna
authors.initials: A
authors.lastname: George
authors.forename: Vineeta
authors.initials: V
authors.lastname: Bal
authors.forename: Jeannine M
authors.initials: JM
authors.lastname: Durdik
authors.forename: Satyajit
authors.initials: S
authors.lastname: Rath
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases