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

Abstract

UNLABELLED:

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.

IMPORTANCE:

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: Haifeng C Xu, Jun Huang, Vishal Khairnar, Vikas Duhan, Aleksandra A Pandyra, Melanie Grusdat, Prashant Shinde, David R McIlwain, Sathish Kumar Maney, Jennifer Gommerman, Max Löhning, Pamela S Ohashi, Tak W Mak, Kathrin Pieper, Heiko Sic, Matthaios Speletas, Hermann Eibel, Carl F Ware, Alexei V Tumanov, Andrey A Kruglov, Sergei A Nedospasov, Dieter Häussinger, Mike Recher, Karl S Lang, Philipp A Lang
• Journal: Journal of virology (J Virol) Vol. 89 Issue 9 Pg. 4748-59 (May 2015) ISSN: 1098-5514 [Electronic] United States
• PMID: 25673724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Interferon Type I
• Receptors, Interleukin-4
• Sialic Acid Binding Ig-like Lectin 1
• Siglec1 protein, mouse

Topics

• Adaptive Immunity
• Animals
• Arenaviridae Infections (immunology)
• Immunity, Innate
• Interferon Type I (metabolism)
• Lymphocytic choriomeningitis virus (immunology)
• Macrophages (chemistry, immunology)
• Mice, Knockout
• Receptors, Interleukin-4 (deficiency)
• Rhabdoviridae Infections (immunology)
• Sialic Acid Binding Ig-like Lectin 1 (analysis)
• Signal Transduction
• Vesiculovirus (immunology)