title: Essential role for autophagy during invariant NKT cell development.
abstract: Autophagy is an evolutionarily conserved cellular homeostatic pathway essential for development, immunity, and cell death. Although autophagy modulates MHC antigen presentation, it remains unclear whether autophagy defects impact on CD1d lipid loading and presentation to invariant natural killer T (iNKT) cells and on iNKT cell differentiation in the thymus. Furthermore, it remains unclear whether iNKT and conventional T cells have similar autophagy requirements for differentiation, survival, and/or activation. We report that, in mice with a conditional deletion of the essential autophagy gene Atg7 in the T-cell compartment (CD4 Cre-Atg7(-/-)), thymic iNKT cell development--unlike conventional T-cell development--is blocked at an early stage and mature iNKT cells are absent in peripheral lymphoid organs. The defect is not due to altered loading of intracellular iNKT cell agonists; rather, it is T-cell-intrinsic, resulting in enhanced susceptibility of iNKT cells to apoptosis. We show that autophagy increases during iNKT cell thymic differentiation and that it developmentally regulates mitochondrial content through mitophagy in the thymus of mice and humans. Autophagy defects result in the intracellular accumulation of mitochondrial superoxide species and subsequent apoptotic cell death. Although autophagy-deficient conventional T cells develop normally, they show impaired peripheral survival, particularly memory CD8(+) T cells. Because iNKT cells, unlike conventional T cells, differentiate into memory cells while in the thymus, our results highlight a unique autophagy-dependent metabolic regulation of adaptive and innate T cells, which is required for transition to a quiescent state after population expansion.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom; mariolina.salio@imm.ox.ac.uk.
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Puleston
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Till S M
authors.initials: TS
authors.lastname: Mathan
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Stranks
authors.affiliation: Developmental Immunology, Department of Pediatrics, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Eleni
authors.initials: E
authors.lastname: Adamopoulou
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B11 2TT, United Kingdom; and.
authors.forename: Natacha
authors.initials: N
authors.lastname: Veerapen
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B11 2TT, United Kingdom; and.
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.affiliation: Developmental Immunology, Department of Pediatrics, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom; Laboratory of Pediatric Immunology, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Hollander
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071193:Autophagy-Related Protein 7; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D013481:Superoxides / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D013481:Superoxides; D000071193:Autophagy-Related Protein 7
keywords: CD1d; autophagy; glycolysis; iNKT cells; metabolism