title: Survival of effector CD8+ T cells during influenza infection is dependent on autophagy.
abstract: The activation and expansion of effector CD8(+) T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known. In this study, we generated a novel inducible autophagy knockout mouse to study T cell effector responses during the course of a virus infection. In response to influenza infection, Atg5(-/-) CD8(+) T cells had a decreased capacity to reach the peak effector response and were unable to maintain cell viability during the effector phase. As a consequence of Atg5 deletion and the impairment in effector-to-memory cell survival, mice fail to mount a memory response following a secondary challenge. We found that Atg5(-/-) effector CD8(+) T cells upregulated p53, a transcriptional state that was concomitant with widespread hypoxia in lymphoid tissues of infected mice. The onset of p53 activation was concurrent with higher levels of reactive oxygen species (ROS) that resulted in ROS-dependent apoptotic cell death, a fate that could be rescued by treating with the ROS scavenger N-acetylcysteine. Collectively, these results demonstrate that effector CD8(+) T cells require autophagy to suppress cell death and maintain survival in response to a viral infection.
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada;
authors.forename: Katrin
authors.initials: K
authors.lastname: Schlie
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada;
authors.forename: Ashley
authors.initials: A
authors.lastname: Westerback
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada;
authors.forename: Lindsay
authors.initials: L
authors.lastname: DeVorkin
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada;
authors.forename: Luke R
authors.initials: LR
authors.lastname: Hughson
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada;
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Brandon
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada;
authors.forename: Sarah
authors.initials: S
authors.lastname: MacPherson
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Izabelle
authors.initials: I
authors.lastname: Gadawski
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada;
authors.forename: Katelin N
authors.initials: KN
authors.lastname: Townsend
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada;
authors.forename: Vincent I
authors.initials: VI
authors.lastname: Poon
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada;
authors.forename: Mary A
authors.initials: MA
authors.lastname: Elrick
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Helene C F
authors.initials: HC
authors.lastname: Côté
authors.affiliation: Department of Zoology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Ninan
authors.identifier: http://orcid.org/0000-0002-2747-1246
authors.initials: N
authors.lastname: Abraham
authors.affiliation: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada; jjlum@bccancer.bc.ca.
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Lum
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D000860:Hypoxia / Q000378:metabolism; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53