title: Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes.
abstract: Autophagy is implicated in many functions of mammalian cells such as organelle recycling, survival and differentiation, and is essential for the maintenance of T and B lymphocytes. Here, we demonstrate that autophagy is a constitutive process during T cell development. Deletion of the essential autophagy genes Atg5 or Atg7 in T cells resulted in decreased thymocyte and peripheral T cell numbers, and Atg5-deficient T cells had a decrease in cell survival. We employed functional-genetic and integrative computational analyses to elucidate specific functions of the autophagic process in developing T-lineage lymphocytes. Our whole-genome transcriptional profiling identified a set of 699 genes differentially expressed in Atg5-deficient and Atg5-sufficient thymocytes (Atg5-dependent gene set). Strikingly, the Atg5-dependent gene set was dramatically enriched in genes encoding proteins associated with the mitochondrion. In support of a role for autophagy in mitochondrial maintenance in T lineage cells, the deletion of Atg5 led to increased mitochondrial mass in peripheral T cells. We also observed a correlation between mitochondrial mass and Annexin-V staining in peripheral T cells. We propose that autophagy is critical for mitochondrial maintenance and T cell survival. We speculate that, similar to its role in yeast or mammalian liver cells, autophagy is required in T cells for the removal of damaged or aging mitochondria and that this contributes to the cell death of autophagy-deficient T cells.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Stephenson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Miller
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.forename: Jason
authors.initials: J
authors.lastname: Eisenberg
authors.forename: Zijiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Ken
authors.initials: K
authors.lastname: Cadwell
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Noboru N
authors.initials: NN
authors.lastname: Mizushima
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D000818:Animals; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D019295:Computational Biology; D030541:Databases, Genetic; D016678:Genome / Q000235:genetics; D019426:Integrases / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D053142:Mitochondrial Size; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; C045073:Cre recombinase; D019426:Integrases; D000071193:Autophagy-Related Protein 7