期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 131, 期 3, 页码 815-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.08.050
关键词
Type I interferon; dendritic cells; CD8 T cells; virus; Wiskott-Aldrich syndrome protein; Wiskott-Aldrich syndrome; diabetes
资金
- Swiss National Science Foundation [3100A0-100779, 3100A0-100068]
- Sonderforschungsbereich [SFB575, SFB974]
- Deutsche Forschungsgemeinschaft [SCHE692/3-1, LA1419/3-1]
- MOI graduate school (Jurgen Manchot Stiftung)
- Great Ormond Street Hospital Childrens Charity
- Wellcome Trust [057965/Z/99/B, 075880]
- European Commission [IEF 040855]
- Canadian Institute of Health Research [FRN79434]
- Alexander von Humboldt Foundation
- German Research Foundation (DFG)
- Swiss National Science Foundation
- Canadian Institutes of Health Research
- Terry Fox Foundation
- CIHR and Genome Canada
- Great Ormond Street Hospital Childrens Charity [V1223, V1259] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10001] Funding Source: researchfish
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 KODCs 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. (J Allergy Clin Immunol 2013;131:815-24.)
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