FcµR and IgM‐Mediated Complement Activation Cooperate to Enhance Humoral Immunity

Secretory IgM plays a pivotal role in promoting robust antigen-specific IgG responses, yet the mechanisms underlying its immune-enhancing effects remain incompletely understood. IgM functions through two distinct pathways: engagement of the IgM Fc receptor (FcµR) and activation of the classical complement pathway. However, the extent of redundancy between these pathways and their roles at different stages of B cell differentiation remains unclear. To address this, we utilized FcµR-deficient mice and Cµ13 mice, which express mutant IgM incapable of activating complement. Both strains exhibited impaired T-dependent immune responses to low-dose 4-hydroxy-3-nitrophenyl-chicken γ globulin. Remarkably, FcµR^-/-Cµ13 double-mutant mice showed profound defects in antigen-specific IgG production compared with either single mutant, revealing nonredundant, synergistic roles for FcµR and complement. Mechanistically, both pathways are required for early B cell activation and expansion, promoting efficient class switch recombination, germinal center (GC) formation, and plasma cell differentiation. During the GC response, IgM BCR-mediated complement activation, but not FcµR, is required for GC B-cell proliferation, survival, and affinity maturation. In contrast, FcµR primarily enhances BCR signaling in naïve B cells through downstream PI3K-AKT and MAPK pathways. These findings define two cooperative yet distinct IgM-mediated mechanisms that promote humoral immunity and regulate B cell differentiation in vivo.