Phagocytosis of enterovirus-infected pancreatic beta-cells triggers innate immune responses in human dendritic cells

  1. Barbara M. Schulte1,
  2. Matthijs Kramer2,
  3. Marleen Ansems2,
  4. Kjerstin H.W. Lanke1,
  5. Neeltje van Doremalen1,
  6. Jon D. Piganelli3,
  7. Rita Bottino3,
  8. Massimo Trucco3,
  9. Jochem M.D. Galama1,
  10. Gosse J. Adema2 and
  11. Frank J.M. van Kuppeveld (f.vankuppeveld{at}ncmls.ru.nl)1
  1. Departments of 1Medical Microbiology and
  2. 2Tumor Immunology, Nijmegen Centre for Molecular Life Sciences and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  3. 3Diabetes Institute, Department of Pediatrics, University of Pittsburgh, Pittsburgh, USA

Abstract

Background. 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).

Objective. To investigate the interaction between enterovirus-infected human pancreatic islets and human DCs.

Research Design and 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 qPCR and western blotting of interferon-stimulated genes (ISGs).

Results. 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 RIG-I-like helicases (RLHs) RIG-I and 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 (IFN)-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.

Footnotes

    • Received July 22, 2009.
    • Accepted January 6, 2010.