title: Role of apoptosis-inducing factor (Aif) in the T cell lineage.
abstract: Multiple checkpoints regulating finely balanced death-versus-survival decisions characterize both thymic development and peripheral homeostasis of T lymphocytes. While exploring the mechanisms of T cell death involved at various stages during the life of a T cell, we have observed and reported a variety of non-redundant roles for apoptosis inducing factor (Aif), a mitochondrial flavoprotein. Aif is ubiquitously expressed in all cell lineages and functions as an NADH oxidase in its mitochondrial location. It is released following the mitochondrial death signals, whereupon it translocates to the nucleus, binds to DNA and causes large-scale DNA fragmentation. During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS). In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID). Thus, Aif seems to have pro-apoptotic and anti-apoptotic roles in the same lineage in different contexts and at different stages. Surprisingly, in the closely related B lymphocyte lineage, Aif deficiency does not result in any abnormality. These findings generate the possibility of specific T cell dysfunction in human disease caused by Aif deficiency, as well as in mitochondriopathies due to other causes. Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.
authors.affiliation: National Institute of Immunology, New Delhi, India, .
authors.forename: Savit B
authors.initials: SB
authors.lastname: Prabhu
authors.forename: Jasneet K
authors.initials: JK
authors.lastname: Khalsa
authors.forename: Hridesh
authors.initials: H
authors.lastname: Banerjee
authors.forename: Abhishek
authors.initials: A
authors.lastname: Das
authors.forename: Smita
authors.initials: S
authors.lastname: Srivastava
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Mattoo
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Thyagarajan
authors.forename: Shalini
authors.initials: S
authors.lastname: Tanwar
authors.forename: Deepika S
authors.initials: DS
authors.lastname: Das
authors.forename: Subeer S
authors.initials: SS
authors.lastname: Majumdar
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.affiliation: National Institute of Immunology, New Delhi, India, .
authors.forename: Satyajit
authors.initials: S
authors.lastname: Rath
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000276:immunology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000254:growth & development* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D009097:Multienzyme Complexes; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases