Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency

J Allergy Clin Immunol. 2013 Mar;131(3):815-24. doi: 10.1016/j.jaci.2012.08.050. Epub 2012 Nov 6.

Abstract

Background: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by absence of Wiskott-Aldrich syndrome protein (WASP) expression, resulting in defective function of many immune cell lineages and susceptibility to severe bacterial, viral, and fungal infections. Despite a significant proportion of patients with WAS having recurrent viral infections, surprisingly little is known about the effects of WASP deficiency on antiviral immunity.

Objective: We sought to evaluate the antiviral immune response in patients with WASP deficiency in vivo.

Methods: Viral clearance and associated immunopathology were measured after infection of WASP-deficient (WAS KO) mice with lymphocytic choriomeningitis virus (LCMV). Induction of antiviral CD8(+) T-cell immunity and cytotoxicity was documented in WAS KO mice by means of temporal enumeration of total and antigen-specific T-cell numbers. Type I interferon (IFN-I) production was measured in serum in response to LCMV challenge and characterized in vivo by using IFN-I reporter mice crossed with WAS KO mice.

Results: WAS KO mice showed reduced viral clearance and enhanced immunopathology during LCMV infection. This was attributed to both an intrinsic CD8(+) T-cell defect and defective priming of CD8(+) T cells by dendritic cells (DCs). IFN-I production by WAS KO DCs was reduced both in vivo and in vitro.

Conclusions: These studies use a well-characterized model of persistence-prone viral infection to reveal a critical deficiency of CD8(+) T-cell responses in murine WASP deficiency, in which abrogated production of IFN-I by DCs might play an important contributory role. These findings might help us to understand the immunodeficiency of WAS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arenaviridae Infections / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Dendritic Cells / immunology*
  • Disease Models, Animal
  • Humans
  • Interferon Type I / immunology*
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rhabdoviridae Infections / immunology*
  • Vesicular stomatitis Indiana virus
  • Wiskott-Aldrich Syndrome / immunology
  • Wiskott-Aldrich Syndrome Protein / deficiency
  • Wiskott-Aldrich Syndrome Protein / genetics
  • Wiskott-Aldrich Syndrome Protein / immunology*

Substances

  • Interferon Type I
  • Wiskott-Aldrich Syndrome Protein