title: Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T-cell development and function.
abstract: Mutations in PTEN-induced kinase 1 (PINK1), a serine/threonine kinase linked to familial early-onset Parkinsonism, compromise mitochondrial integrity and metabolism and impair AKT signaling. As the activation of a naïve T cell requires an AKT-dependent reorganization of a cell's metabolic machinery, we sought to determine if PINK1-deficient T cells lack the ability to undergo activation and differentiation. We show that CD4(+) T cells from PINK1 knockout mice fail to properly phosphorylate AKT upon activation, resulting in reduced expression of the IL-2 receptor subunit CD25. Following, deficient IL-2 signaling mutes the activation-induced increase in respiratory capacity and mitochondrial membrane potential. Under polarization conditions favoring the development of induced regulatory T cells, PINK1(-/-) T cells exhibit a reduced ability to suppress bystander T-cell proliferation despite normal FoxP3 expression kinetics. Our results describe a critical role for PINK1 in integrating extracellular signals with metabolic state during T-cell fate determination, and may have implications for the understanding of altered T-cell populations and immunity during the progression of active Parkinson's disease or other immunopathologies.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Ellis
authors.forename: Lianteng
authors.initials: L
authors.lastname: Zhi
authors.forename: Ravi
authors.initials: R
authors.lastname: Akundi
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Büeler
authors.forename: Francesc
authors.initials: F
authors.lastname: Marti
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003600:Cytosol / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000276:immunology*; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099202:PTEN-Induced Putative Kinase; C498833:Foxp3 protein, mouse
keywords: AKT signaling; Parkinson's disease; Peripheral T‐cell differentiation; Regulatory T (Treg) cells; T‐cell signaling
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