B cell-intrinsic type I interferon signaling contributes to defective antibody responses to a model antigen during...

Affinity maturation and vaccine efficacy are compromised during chronic viral infections; however, underlying mechanisms remain unclear. Using the LCMV Cl13 model, we show that type I interferon (IFN-I) signaling in B cells plays a central role. IFN-I promotes early B cell activation but reduces clonal diversity and delays IgG1⁺ B cell entry into germinal centers (GCs), impairing high-affinity clone selection. Deletion of IFNAR1 in B cells partially restores nitrophenyl (NP)-specific IGHV1-72 and GC access but fails to rescue affinity maturation, suggesting a contribution of extrinsic factors. Somatic hypermutation is elevated in LCMV IFNAR1^+/+ and IFNAR1^-/- genotypes, though slightly less in IFNAR1^-/- B cells. BASELINe analysis indicates weaker selection pressure in complementarity determining regions (CDRs), reflecting impaired affinity-based selection, correlating with a reduced follicular regulatory T cells/follicular helper T cells (TFR/TFH) ratio. Our results show that intrinsic and extrinsic IFN-I-dependent mechanisms synergize to disrupt B cell fate, establishing IFN-I as a key regulator of humoral immunity and highlighting mechanisms underlying poor vaccine response during persistent viral infection.