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
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Mentions: To investigate which cells were responsible for the defective production of IFN-Is, we made use of the IFN-β reporter–knock-in mouse, in which yellow fluorescent protein (YFP) expression is bicistronically linked to expression of IFN-β of the endogenous ifnb locus, so that IFN-β–producing cells can easily be identified by using YFP expression.46 These IFNβmob/mob mice were crossed with WAS KO mice and challenged with Poly(I:C). As expected, we found that in the absence of WASP, IFN-β/YFP expression was reduced in splenocytes and that this was restricted to CD11c+ cells (Fig 6, A and B). To verify that this was not caused by an overall reduction in the number of DCs in WAS KO mice, we analyzed the proportion of conventional migratory (cDCs; CD11c+CD11b+CD8α−B220−), conventional CD8α+ (CD11c+CD11b−CD8α+B220−), and plasmacytoid (pDCs; CD11c+CD11b−B220+ or CD11c+mPDCA1+) DC subsets. As expected from previous reports,14,47 we did not observe significant differences between distinct subsets in spleens or lymph nodes in C57BL/6 or WAS KO mice (Fig 6, C and D, and see Fig E2, A, in this article's Online Repository at www.jacionline.org). Total splenocyte and lymph node cell numbers in WAS KO and C57BL/6 mice were comparable, as were absolute cell counts of DC subsets (see Fig E2, B-E). Finally, we tested whether the impaired production of IFN-I observed in vivo reflected an intrinsic deficiency of DCs in the absence of WASP. Both pDCs and cDCs showed a reduced IFN-α response when stimulated with Poly(I:C), CpG, and LPS in vitro (Fig 6, E). Similarly, when we used ex vivo–isolated splenic CD11c+ cells, a similar deficiency in IFN-α production in response to Poly(I:C), LPS, and CpG was observed (see Fig E2, F). These findings show that WAS KO DCs are intrinsically compromised in their ability to secrete IFN-I.
Affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.