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Severely impaired CTL killing is a feature of the neurological disorder Niemann-Pick disease type C1.
Castiblanco, Daniela; Rudd-Schmidt, Jesse A; Noori, Tahereh; Sutton, Vivien R; Hung, Ya Hui; Flinsenberg, Thijs W H; Hodel, Adrian W; Young, Neil D; Smith, Nicholas; Bratkovic, Drago; Peters, Heidi; Walterfang, Mark; Trapani, Joseph A; Brennan, Amelia J; Voskoboinik, Ilia.
Afiliação
  • Castiblanco D; Killer Cell Biology Laboratory and.
  • Rudd-Schmidt JA; Killer Cell Biology Laboratory and.
  • Noori T; Killer Cell Biology Laboratory and.
  • Sutton VR; Cancer Cell Death Laboratory, Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Hung YH; Oxidation Biology Unit, Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health and University of Melbourne, Parkville, Australia.
  • Flinsenberg TWH; Killer Cell Biology Laboratory and.
  • Hodel AW; Killer Cell Biology Laboratory and.
  • Young ND; Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Australia.
  • Smith N; Neurology and Clinical Neurophysiology, Women's and Children's Hospital, North Adelaide, Australia.
  • Bratkovic D; Paediatric Neurodegenerative Disease Research Group, Discipline of Paediatrics, University of Adelaide, Adelaide, Australia.
  • Peters H; Metabolic Clinic, Women's and Children's Hospital, North Adelaide, Australia.
  • Walterfang M; Metabolic Medicine, Royal Children's Hospital, Parkville, Australia.
  • Trapani JA; Oxidation Biology Unit, Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health and University of Melbourne, Parkville, Australia.
  • Brennan AJ; Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Australia; and.
  • Voskoboinik I; Melbourne Neuropsychiatry Centre and.
Blood ; 139(12): 1833-1849, 2022 03 24.
Article em En | MEDLINE | ID: mdl-35081253
Niemann-Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder resulting from mutations in an endolysosomal cholesterol transporter, NPC1. Despite typically presenting with pronounced neurological manifestations, NP-C1 also resembles long-term congenital immunodeficiencies that arise from impairment of cytotoxic T lymphocyte (CTL) effector function. CTLs kill their targets through exocytosis of the contents of lysosome-like secretory cytotoxic granules (CGs) that store and ultimately release the essential pore-forming protein perforin and proapoptotic serine proteases, granzymes, into the synapse formed between the CTL and target cell. We discovered that NPC1 deficiency increases CG lipid burden, impairs autophagic flux through stalled trafficking of the transcription factor EB (TFEB), and dramatically reduces CTL cytotoxicity. Using a variety of immunological and cell biological techniques, we found that the cytotoxic defect arises specifically from impaired perforin pore formation. We demonstrated defects of CTL function of varying severity in patients with NP-C1, with the greatest losses of function associated with the most florid and/or earliest disease presentations. Remarkably, perforin function and CTL cytotoxicity were restored in vitro by promoting lipid clearance with therapeutic 2-hydroxypropyl-ß-cyclodextrin; however, restoration of autophagy through TFEB overexpression was ineffective. Overall, our study revealed that NPC1 deficiency has a deleterious impact on CTL (but not natural killer cell) cytotoxicity that, in the long term, may predispose patients with NP-C1 to atypical infections and impaired immune surveillance more generally.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Niemann-Pick Tipo A / Doença de Niemann-Pick Tipo C Limite: Humans Idioma: En Revista: Blood Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Niemann-Pick Tipo A / Doença de Niemann-Pick Tipo C Limite: Humans Idioma: En Revista: Blood Ano de publicação: 2022 Tipo de documento: Article