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

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).Weidentified 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.