The ubiquitin ligase Cul4b is essential for antibody-mediated protection against Influenza A virus infection 3941

Abstract Description Influenza A virus (IAV)-specific antibodies (Abs) are secreted by plasma cells (PC) after viral infection or vaccination. B cells undergo affinity maturation prior to PC differentiation in germinal centers (GC), enduring rounds of somatic hypermutation (SHM), proliferation, and selection to gain high affinity. This requires stringent regulation of DNA damage response and cell cycle. Cullin4b (Cul4b), the backbone of an E3 ubiquitin ligase complex, ubiquitylates proteins for degradation to regulate cell cycle and DNA damage. As both processes are integral to GC B cell biology, we hypothesized that Cul4b promotes protective Ab responses by supporting affinity maturation. To test this, we immunized B cell-specific Cul4b knockout (cKO) mice and wild-type littermate controls with an mRNA vaccine encoding hemagglutinin from PR8, a mouse adapted H1N1 IAV. In Cul4b cKO groups, we found reduced IAV-specific Ab titers, fewer GC B cells, and impaired protection after homologous challenge, suggesting Cul4b promotes optimal Ab titers and immune protection. We also show that Cul4b supports high affinity Ab production and cell cycle in antigen-specific GC B cells. We believe Cul4b supports antiviral immunity by regulating cell cycle in GC B cells during SHM to promote formation of high affinity neutralizing Abs. Cul4b is a novel facilitator of protective Ab responses to viruses and a potential target for vaccines. Funding Sources American Lung Association Topic Categories Viral Immunology (VIR)