title: Phagocytosis of enterovirus-infected pancreatic beta-cells triggers innate immune responses in human dendritic cells.
abstract: OBJECTIVE
  Type 1 diabetes is a chronic endocrine disorder in which enteroviruses, such as coxsackie B viruses and echoviruses, are possible environmental factors that can trigger or accelerate disease. The development or acceleration of type 1 diabetes depends on the balance between autoreactive effector T-cells and regulatory T-cells. This balance is particularly influenced by dendritic cells (DCs). The goal of this study was to investigate the interaction between enterovirus-infected human pancreatic islets and human DCs.
  
  
  METHODS
  In vitro phagocytosis of human or porcine primary islets or Min6 mouse insuloma cells by DCs was investigated by flow cytometry and confocal analysis. Subsequent innate DC responses were monitored by quantitative PCR and Western blotting of interferon-stimulated genes (ISGs).
  
  
  RESULTS
  In this study, we show that both mock- and coxsackievirus B3 (CVB3)-infected human and porcine pancreatic islets were efficiently phagocytosed by human monocyte-derived DCs. Phagocytosis of CVB3-infected, but not mock-infected, human and porcine islets resulted in induction of ISGs in DCs, including the retinoic acid-inducible gene (RIG)-I-like helicases (RLHs), RIG-I, and melanoma differentiation-associated gene 5 (Mda5). Studies with murine Min6 insuloma cells, which were also efficiently phagocytosed, revealed that increased ISG expression in DCs upon encountering CVB-infected cells resulted in an antiviral state that protected DCs from subsequent enterovirus infection. The observed innate antiviral responses depended on RNA within the phagocytosed cells, required endosomal acidification, and were type I interferon dependent.
  
  
  CONCLUSIONS
  Human DCs can phagocytose enterovirus-infected pancreatic cells and subsequently induce innate antiviral responses, such as induction of RLHs. These responses may have important consequences for immune homeostasis in vivo and may play a role in the etiology of type 1 diabetes.
authors.affiliation: Department of Medical Microbiology, Nijmegen Centre for Molecular Life Sciences and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Schulte
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kramer
authors.forename: Marleen
authors.initials: M
authors.lastname: Ansems
authors.forename: Kjerstin H W
authors.initials: KH
authors.lastname: Lanke
authors.forename: Neeltje
authors.initials: N
authors.lastname: van Doremalen
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.forename: Jochem M D
authors.initials: JM
authors.lastname: Galama
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: van Kuppeveld
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004770:Enterovirus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000276:immunology / Q000821:virology*; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology / Q000821:virology; D051379:Mice; D010587:Phagocytosis / Q000276:immunology*; D013552:Swine; D014407:Tumor Cells, Cultured