title: Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps34.
abstract: Autophagy plays a critical role in multiple aspects of the immune system, including the development and function of T lymphocytes. In mammalian cells, the class III PI3K vacuolar protein sorting (Vps)34 is thought to play a critical role in autophagy. However, recent studies have cast doubt on the role of Vps34 in autophagy, at least in certain cell types. To study the effects of Vps34 on autophagy in T lymphocytes, we generated mice that selectively lack Vps34 in the T cell lineage. Vps34 ablation in T cells caused profound defects in autophagic flux, resulting in accumulation of cellular organelles and apoptosis. These animals exhibited normal intrathymic development of conventional T cells, but they were profoundly impaired in the intrathymic development of invariant NKT cells. In peripheral organs, T cell-specific ablation of Vps34 had a profound impact on T cell homeostasis and function. Furthermore, aged animals developed an inflammatory wasting syndrome characterized by weight loss, intestinal inflammation, and anemia. Consistent with this phenotype, Vps34 was required for the peripheral maintenance and function of CD4(+)Foxp3(+) regulatory T cells. Collectively, our study reveals a critical role for Vps34 in autophagy and for the peripheral homeostasis and function of T lymphocytes.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. vrajesh.v.parekh@vanderbilt.edu
authors.forename: Vrajesh V
authors.initials: VV
authors.lastname: Parekh
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: Janice A
authors.initials: JA
authors.lastname: Williams
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Gaddy
authors.forename: Danyvid
authors.initials: D
authors.lastname: Olivares-Villagómez
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Cover
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
mesh_terms: D019264:Adoptive Transfer; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics*; D003092:Colitis / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019282:Wasting Syndrome / Q000235:genetics* / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D058546:Class III Phosphatidylinositol 3-Kinases