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

• Published in: Journal of allergy and clinical immunology 2013-03, Vol.131 (3), p.815-824.e2
• Main Authors: Lang, Philipp A., MD, PhD, Shaabani, Namir, MSc, Borkens, Stephanie, MSc, Honke, Nadine, MSc, Scheu, Stefanie, PhD, Booth, Sarah, MSc, Brenner, Dirk, PhD, Meryk, Andreas, MSc, Barthuber, Carmen, MD, PhD, Recher, Mike, MD, Mak, Tak W., PhD, Ohashi, Pamela S., PhD, Häussinger, Dieter, MD, Griffiths, Gillian M., PhD, Thrasher, Adrian J., MD, PhD, Bouma, Gerben, PhD, Lang, Karl S., MD, PhD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Arenaviridae Infections - immunology; Biological and medical sciences; CD8 T cells; CD8-Positive T-Lymphocytes - immunology; Cytotoxicity; dendritic cells; Dendritic Cells - immunology; diabetes; Disease Models, Animal; Experiments; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Hematologic and hematopoietic diseases; Herpes viruses; Homeostasis; Humans; Immune Deficiencies, Infection, and Systemic Immune Disorders; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infections; Interferon; Interferon Type I - immunology; Lymphocytes; Lymphocytic choriomeningitis virus; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet diseases and coagulopathies; Rhabdoviridae Infections - immunology; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; T cell receptors; Transcription factors; Type I interferon; Vesicular stomatitis Indiana virus; Viral infections; virus; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome - immunology; Wiskott-Aldrich syndrome protein; Wiskott-Aldrich Syndrome Protein - deficiency; Wiskott-Aldrich Syndrome Protein - genetics; Wiskott-Aldrich Syndrome Protein - immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.08.050

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.