title: Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.
abstract: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.
  
  
  OBJECTIVE
  Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.
authors: Campell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Haifeng C
authors: HC
authors: Xu
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
authors: Jun
authors: J
authors: Huang
authors: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Vishal
authors: V
authors: Khairnar
authors: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Vikas
authors: V
authors: Duhan
authors: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Aleksandra A
authors: AA
authors: Pandyra
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
authors: Melanie
authors: M
authors: Grusdat
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
authors: Prashant
authors: P
authors: Shinde
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, California, USA.
authors: David R
authors: DR
authors: McIlwain
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
authors: Sathish Kumar
authors: SK
authors: Maney
authors: Department of Immunology, University of Toronto, Toronto, Ontario Canada.
authors: Jennifer
authors: J
authors: Gommerman
authors: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Berlin, Germany German Rheumatism Research Center (DRFZ), Leibniz Institute, Berlin, Germany.
authors: Max
authors: M
authors: Löhning
authors: Campell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada Department of Immunology, University of Toronto, Toronto, Ontario Canada.
authors: Pamela S
authors: PS
authors: Ohashi
authors: Campell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada Department of Immunology, University of Toronto, Toronto, Ontario Canada.
authors: Tak W
authors: TW
authors: Mak
authors: University Medical Centre Freiburg, Center of Chronic Immunodeficiency Freiburg, Freiburg, Germany.
authors: Kathrin
authors: K
authors: Pieper
authors: University Medical Centre Freiburg, Center of Chronic Immunodeficiency Freiburg, Freiburg, Germany.
authors: Heiko
authors: H
authors: Sic
authors: Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, Larissa, Greece.
authors: Matthaios
authors: M
authors: Speletas
authors: University Medical Centre Freiburg, Center of Chronic Immunodeficiency Freiburg, Freiburg, Germany.
authors: Hermann
authors: H
authors: Eibel
authors: Sanford Burnham Medical Research Institute, La Jolla, California, USA.
authors: Carl F
authors: CF
authors: Ware
authors: Trudeau Institute, Saranac Lake, New York, USA.
authors: Alexei V
authors: AV
authors: Tumanov
authors: German Rheumatism Research Center (DRFZ), Leibniz Institute, Berlin, Germany.
authors: Andrey A
authors: AA
authors: Kruglov
authors: German Rheumatism Research Center (DRFZ), Leibniz Institute, Berlin, Germany Lomonosov Moscow State University, Moscow, Russia.
authors: Sergei A
authors: SA
authors: Nedospasov
authors: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
authors: Dieter
authors: D
authors: Häussinger
authors: Primary Immunodeficiency Clinic, Medical Outpatient Division and Immunodeficiency Laboratory, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors: Mike
authors: M
authors: Recher
authors: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Karl S
authors: KS
authors: Lang
authors: Campell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany Department of Molecular Medicine II, Düsseldorf, Germany Philipp.Lang@med.uni-duesseldorf.de.
authors: Philipp A
authors: PA
authors: Lang
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008264:Macrophages / Q000737:chemistry* / Q000276:immunology*; D018345:Mice, Knockout; D019948:Receptors, Interleukin-4 / Q000172:deficiency*; D018353:Rhabdoviridae Infections / Q000276:immunology*; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000032:analysis*; D015398:Signal Transduction; D018116:Vesiculovirus / Q000276:immunology
chemical_list: D007370:Interferon Type I; D019948:Receptors, Interleukin-4; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse