The ubiquitin ligase Cul4b drives B cell proliferation and antiviral antibody responses 3736

Abstract Description High affinity neutralizing antibodies (Abs) are essential for immune protection against Influenza A virus (IAV) infection. Affinity maturation occurs in germinal centers (GC), where activated B cells undergo proliferation, somatic hypermutation, and selection. This requires high levels of DNA damage while maintaining a rapid proliferation rate. Cullin 4b (Cul4b) is an E3 ubiquitin ligase found in most cells that regulates cell cycle maintenance and responses to DNA damage. Cul4b serves as a docking protein for the Cullin RING Ligase 4 (CRL4) complex, which ubiquitinates substrate proteins for degradation. Because proliferation and DDR are essential for humoral immunity, we hypothesize that Cul4b also functions in GC B cells. To test this, we infected mice lacking Cul4b in B cells (KO) and wild-type (WT) controls with a mouse adapted H1N1 Influenza A virus (IAV), PR8. We measured GC B cells and IAV-specific serum Abs. We found these to be dramatically reduced in Cul4b KO mice. We also tested if B cells need Cul4b for clonal expansion by stimulating WT and KO B cells to proliferate in vitro in the presence of ultraviolet (UV) induced DNA damage. We found Cul4b promotes B cell proliferation after UV exposure. Understanding how Cul4b promotes B cell clonal expansion in the face of DNA damage will identify new targets to transiently amplify this pathway. This may be used to improve vaccines by encouraging Ab responses or can be inhibited to prevent tumor progression in cancer. Funding Sources American Lung Association Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)