Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency.
Bottom Line: 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.IFN-I production by WAS KO DCs was reduced both in vivo and in vitro.These findings might help us to understand the immunodeficiency of WAS.
Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.Show MeSH
Related in: MedlinePlus
Mentions: Because T cells require antigen-specific stimulation by DCs for optimal priming, we investigated the contribution of defective DC-mediated T-cell priming to abnormal CD8+ T-cell responses. We adoptively transferred bone marrow–derived WAS KO DCs pulsed with ovalbumin into wild-type C57BL/6 recipients and analyzed the antigen-specific IFN-γ response. Both in spleens and draining lymph nodes, we observed reduced numbers of IFN-γ–producing wild-type CD8+ T cells in response to secondary challenge with ovalbumin (Fig 4, A and B), suggesting that defective priming by DCs at least in part contributes to defective function of WAS KO CD8+ T cells. Priming of virus-specific CD8+ T cells is also strongly dependent on IFN-Is, acting either directly on the CD8+ T cells or by maturing DCs necessary for antiviral T-cell immunity.44,45 Accordingly, we analyzed the IFN-I response in WAS KO mice after infection with LCMV. Induction of serum IFN-α was significantly abrogated in WAS KO mice in response to LCMV infection (Fig 5, A). Similarly, when we infected mice with VSV or administered the nonviral, nonreplicating, IFN-I stimulator Toll-like receptor (TLR) 3/RIG-I ligand Poly(I:C) in vivo, WAS KO mice exhibited a markedly diminished IFN-α response (Fig 5, B and C). These findings indicate a general reduction in stimulated IFN-I production in vivo in the absence of WASP expression.
Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.