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

Lang PA, Shaabani N, Borkens S, Honke N, Scheu S, Booth S, Brenner D, Meryk A, Barthuber C, Recher M, Mak TW, Ohashi PS, Häussinger D, Griffiths GM, Thrasher AJ, Bouma G, Lang KS - J. Allergy Clin. Immunol. (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

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Related in: MedlinePlus

WASP deficiency leads to a reduced IFN-α response. Mice were infected with 200 pfu of the LCMV strain WE (A), 2 × 106 pfu VSV (B), or 200 μg of Poly(I:C) (C), and IFN-α levels were measured in serum at the indicated time points. Data are shown as means ± SEMs (LCMV, n = 6-11; VSV, n = 3; Poly[I:C], n = 6). Serum was taken 3 hours after injection.
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fig5: WASP deficiency leads to a reduced IFN-α response. Mice were infected with 200 pfu of the LCMV strain WE (A), 2 × 106 pfu VSV (B), or 200 μg of Poly(I:C) (C), and IFN-α levels were measured in serum at the indicated time points. Data are shown as means ± SEMs (LCMV, n = 6-11; VSV, n = 3; Poly[I:C], n = 6). Serum was taken 3 hours after injection.

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.


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

Lang PA, Shaabani N, Borkens S, Honke N, Scheu S, Booth S, Brenner D, Meryk A, Barthuber C, Recher M, Mak TW, Ohashi PS, Häussinger D, Griffiths GM, Thrasher AJ, Bouma G, Lang KS - J. Allergy Clin. Immunol. (2012)

WASP deficiency leads to a reduced IFN-α response. Mice were infected with 200 pfu of the LCMV strain WE (A), 2 × 106 pfu VSV (B), or 200 μg of Poly(I:C) (C), and IFN-α levels were measured in serum at the indicated time points. Data are shown as means ± SEMs (LCMV, n = 6-11; VSV, n = 3; Poly[I:C], n = 6). Serum was taken 3 hours after injection.
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Related In: Results  -  Collection

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fig5: WASP deficiency leads to a reduced IFN-α response. Mice were infected with 200 pfu of the LCMV strain WE (A), 2 × 106 pfu VSV (B), or 200 μg of Poly(I:C) (C), and IFN-α levels were measured in serum at the indicated time points. Data are shown as means ± SEMs (LCMV, n = 6-11; VSV, n = 3; Poly[I:C], n = 6). Serum was taken 3 hours after injection.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Show MeSH
Related in: MedlinePlus