Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection

• Published in: Journal of virology 2015-05, Vol.89 (9), p.4748-4759
• Main Authors: Xu, Haifeng C, Huang, Jun, Khairnar, Vishal, Duhan, Vikas, Pandyra, Aleksandra A, Grusdat, Melanie, Shinde, Prashant, McIlwain, David R, Maney, Sathish Kumar, Gommerman, Jennifer, Löhning, Max, Ohashi, Pamela S, Mak, Tak W, Pieper, Kathrin, Sic, Heiko, Speletas, Matthaios, Eibel, Hermann, Ware, Carl F, Tumanov, Alexei V, Kruglov, Andrey A, Nedospasov, Sergei A, Häussinger, Dieter, Recher, Mike, Lang, Karl S, Lang, Philipp A
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Arenaviridae Infections - immunology; Cellular Response to Infection; Immunity, Innate; Interferon Type I - secretion; Lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - immunology; Macrophages - chemistry; Macrophages - immunology; Mice, Knockout; Receptors, Interleukin-4 - deficiency; Rhabdoviridae Infections - immunology; Sialic Acid Binding Ig-like Lectin 1 - analysis; Signal Transduction; Vesicular stomatitis virus; Vesiculovirus - immunology
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.02976-14

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. 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.