title: Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1.
abstract: The highly conserved cellular degradation pathway, macroautophagy, regulates the homeostasis of organelles and promotes the survival of T lymphocytes. Previous results indicate that Atg3-, Atg5-, or Pik3c3/Vps34-deficient T cells cannot proliferate efficiently. Here we demonstrate that the proliferation of Atg7-deficient T cells is defective. By using an adoptive transfer and Listeria monocytogenes (LM) mouse infection model, we found that the primary immune response against LM is intrinsically impaired in autophagy-deficient CD8(+) T cells because the cell population cannot expand after infection. Autophagy-deficient T cells fail to enter into S-phase after TCR stimulation. The major negative regulator of the cell cycle in T lymphocytes, CDKN1B, is accumulated in autophagy-deficient naïve T cells and CDKN1B cannot be degraded after TCR stimulation. Furthermore, our results indicate that genetic deletion of one allele of CDKN1B in autophagy-deficient T cells restores proliferative capability and the cells can enter into S-phase after TCR stimulation. Finally, we found that natural CDKN1B forms polymers and is physiologically associated with the autophagy receptor protein SQSTM1/p62 (sequestosome 1). Collectively, autophagy is required for maintaining the expression level of CDKN1B in naïve T cells and selectively degrades CDKN1B after TCR stimulation.
authors.affiliation: a Department of Immunology ; Duke University Medical Center ; Durham ; NC , USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: a Department of Immunology ; Duke University Medical Center ; Durham ; NC , USA.
authors.forename: Ming-Xiao
authors.initials: MX
authors.lastname: He
authors.affiliation: a Department of Immunology ; Duke University Medical Center ; Durham ; NC , USA.
authors.forename: Ian X
authors.initials: IX
authors.lastname: McLeod
authors.affiliation: a Department of Immunology ; Duke University Medical Center ; Durham ; NC , USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: a Department of Immunology ; Duke University Medical Center ; Durham ; NC , USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Ji
authors.affiliation: a Department of Immunology ; Duke University Medical Center ; Durham ; NC , USA.
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
chemical_list: C493961:Cdkn1b protein, mouse; D008869:Microtubule-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: ATG3; ATG7; CDKN1B; T lymphocytes; autophagy; proliferation