title: Atg5 Is Essential for the Development and Survival of Innate Lymphocytes.
abstract: Autophagy is an essential cellular survival mechanism that is required for adaptive lymphocyte development; however, its role in innate lymphoid cell (ILC) development remains unknown. Furthermore, the conditions that promote lymphocyte autophagy during homeostasis are poorly understood. Here, we demonstrate that Atg5, an essential component of the autophagy machinery, is required for the development of mature natural killer (NK) cells and group 1, 2, and 3 innate ILCs. Although inducible ablation of Atg5 was dispensable for the homeostasis of lymphocyte precursors and mature lymphocytes in lymphoreplete mice, we found that autophagy is induced in both adaptive and innate lymphocytes during homeostatic proliferation in lymphopenic hosts to promote their survival by limiting cell-intrinsic apoptosis. Induction of autophagy through metformin treatment following homeostatic proliferation increased lymphocyte numbers through an Atg5-dependent mechanism. These findings highlight the essential role for autophagy in ILC development and lymphocyte survival during lymphopenia.
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: O'Sullivan
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Clair D
authors.initials: CD
authors.lastname: Geary
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Orr-El
authors.initials: OE
authors.lastname: Weizman
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Geiger
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Moritz
authors.initials: M
authors.lastname: Rapp
authors.affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63105, USA.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Overholtzer
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: sunj@mskcc.org.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D006706:Homeostasis; D007113:Immunity, Innate; D008214:Lymphocytes / Q000166:cytology*; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000071187:Autophagy-Related Protein 5; D008687:Metformin