title: Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis.
abstract: The homeostasis of naive T cells is essential for protective immunity against infection, but the cell-intrinsic molecular mechanisms that control naïve T-cell homeostasis are poorly understood. Genetic ablation in lower organisms has revealed a critical role for Vps34, an evolutionary conserved class III phosphoinositide-3 kinase (PI3K), in regulating endocytosis and autophagy; however, the physiological function of Vps34 in the immune system, especially in T cells, is unclear. Here we report that Vps34 is required for the maintenance of naïve T cells, acting in a cell-intrinsic manner. T-cell-specific deletion of the gene encoding Vps34 resulted in reduced stability of Vps15 and Beclin-1, components of the class III PI3K complex, and impaired autophagy in T cells. Vps34 was dispensable for T-cell development but important for the survival of naïve T cells. Vps34-deficient T cells showed increased mitochondrial mass and accumulation of reactive oxygen species, consistent with deficient removal of damaged mitochondria. Thus, Vps34-dependent canonical autophagy plays a critical role in maintaining T-cell homeostasis by promoting T-cell survival through quality control of mitochondria.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Willinger
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D058571:Vacuolar Sorting Protein VPS15 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D017382:Reactive Oxygen Species; D058546:Class III Phosphatidylinositol 3-Kinases; D058571:Vacuolar Sorting Protein VPS15