title: Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency.
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.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Namir
authors.initials: N
authors.lastname: Shaabani
authors.forename: Stephanie
authors.initials: S
authors.lastname: Borkens
authors.forename: Nadine
authors.initials: N
authors.lastname: Honke
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Sarah
authors.initials: S
authors.lastname: Booth
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Andreas
authors.initials: A
authors.lastname: Meryk
authors.forename: Carmen
authors.initials: C
authors.lastname: Barthuber
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Griffiths
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018353:Rhabdoviridae Infections / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D051316:Wiskott-Aldrich Syndrome Protein