Phagocytosis of Enterovirus-Infected Pancreatic β-Cells Triggers Innate Immune Responses in Human Dendritic Cells

  1. Frank J.M. van Kuppeveld1
  1. 1Department of Medical Microbiology, Nijmegen Centre for Molecular Life Sciences and Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands;
  2. 2Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences and Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands;
  3. 3Department of Pediatrics, Diabetes Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
  1. Corresponding author: Frank J.M. van Kuppeveld, f.vankuppeveld{at}ncmls.ru.nl.
  • N.v.D. is currently affiliated with the Health Protection Agency, Colindale, London, U.K.

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.

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 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • See accompanying commentary, p. 1126.

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 59 no. 5 1182-1191
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