Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency - 27/02/13
, Namir Shaabani, MSc b, c, , Stephanie Borkens, MSc d, Nadine Honke, MSc b, c, Stefanie Scheu, PhD d, Sarah Booth, MSc e, Dirk Brenner, PhD a, ‡, 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 Häussinger, MD b, Gillian M. Griffiths, PhD e, ‡, Adrian J. Thrasher, MD, PhD h, i, Gerben Bouma, PhD h, ⁎ 
, Karl S. Lang, MD, PhD b, c, Corresponding author: Gerben Bouma, PhD, Molecular Immunology unit, Institute of Child Health, University College London, 30 Guilford St, London WC1N 1EH, United Kingdom.Abstract |
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 KO DCs 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.
Le texte complet de cet article est disponible en PDF.Key words : Type I interferon, dendritic cells, CD8 T cells, virus, Wiskott-Aldrich syndrome protein, Wiskott-Aldrich syndrome, diabetes
Abbreviations used : cDC, DC, FACS, IFN-I, IL-7R, LCMV, NK, pDC, Poly(I:C), pfu, TLR, VSV, WAS, WAS KO, WASP, YFP
Plan
| Supported by grants from the Swiss National Science Foundation (3100A0-100779 and 3100A0-100068), the Sonderforschungsbereich (SFB575 and SFB974), the Deutsche Forschungsgemeinschaft (SS, SCHE692/3-1 and LA1419/3-1), the MOI graduate school (Jürgen Manchot Stiftung), the Great Ormond Street Hospital Childrens Charity (to A.J.T.), the Wellcome Trust (057965/Z/99/B to A.J.T. and G.B. and 075880 to G.M.G.), the European Commission (Marie Curie IEF 040855 to G.B.), the Canadian Institute of Health Research (FRN79434 to P.S.O.), and the Alexander von Humboldt Foundation (Sofja Kovalevskaja award to K.S.L. and Feodor Lynen award to D.B.). P.S.O. holds a Canada Research Chair in Autoimmunity and Tumor Immunity, and A.J.T. is an NIHR Senior Investigator. |
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| Disclosure of potential conflict of interest: S. Scheu has received research support from the German Research Foundation (DFG). M. Recher has received grants from the Swiss National Science Foundation. T. W. Mak has received grants from the Canadian Institutes of Health Research and the Terry Fox Foundation. P. S. Ohashi has received research support from CIHR and Genome Canada, is employed by the University Health Network, and has received lecture fees from Drexel University. A. J. Thrasher has received research support from the Wellcome Trust. G. Bouma has received research support from the Wellcome Trust and European Commission and received travel expenses from UCL. The rest of the authors declare they have no relevant conflicts of interest. |
Vol 131 - N° 3
P. 815 - mars 2013 Retour au numéro
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