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

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• 作者：Philipp A. Lang ; MD ; PhD^a ; ^b ; ^&lowast ; ; Namir Shaabani ; MSc^b ; ^c ; ^&lowast ; ; Stephanie Borkens ; MSc^d ; Nadine Honke ; MSc^b ; ^c ; Stefanie Scheu ; PhD^d ; Sarah Booth ; MSc^e ; Dirk Brenner ; PhD^a ; ^&Dagger ; ; Andreas Meryk ; MSc^b ; ^c ; Carmen Barthuber ; MD ; PhD^f ; Mike Recher ; MD^g ; Tak W. Mak ; PhD^a ; Pamela S. Ohashi ; PhD^a ; Dieter H&auml ; ussinger ; MD^b ; Gillian M. Griffiths ; PhD^e ; ^&Dagger ; ; Adrian J. Thrasher ; MD ; PhD^h ; ⁱ ; Gerben Bouma ; PhD^h ; ^&lowast ; ; ^{g.bouma@ucl.ac.uk} ; Karl S. Lang ; MD ; PhD^b ; ^c ; ^&lowast ;
• 关键词：Type I interferon ; dendritic cells ; CD8 T cells ; virus ; Wiskott-Aldrich syndrome protein ; Wiskott-Aldrich syndrome ; diabetes
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：131
• 期：3
• 页码：815-824.e2
• 全文大小：1248 K

文摘

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class=""h4"">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.

class=""h4"">Objective

We sought to evaluate the antiviral immune response in patients with WASP deficiency m>in?vivom>.

class=""h4"">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 m>in?vivom> by using IFN-I reporter mice crossed with WAS KO mice.

class=""h4"">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 m>in?vivom> and m>in?vitrom>.

class=""h4"">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.