B Cell-Intrinsic Type I Interferon Signaling Contributes to Defective Vaccine [GEX]

Affinity maturation and vaccine efficacy are compromised during chronic viral infections, yet the underlying mechanisms remain unclear. Using the LCMV Cl13 model, we show that 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, impairing high-affinity clone selection. Deletion of IFNAR1 in B cells partially restores NP-specific IGHV1-72 usage and GC access but fails to fully rescue affinity maturation, suggesting a contribution of extrinsic factors. Somatic hypermutation remains elevated in both genotypes, though slightly reduced in IFNAR1⁻/⁻ B cells. BASELINe analysis indicates weaker selection pressure in CDRs, potentially reflecting impaired affinity-based selection. This defect correlates with a reduced TFR/TFH ratio. Our results show that intrinsic and extrinsic IFN-I-dependent mechanisms synergize to disrupt B cell fate. These findings establish IFN-I as a key regulator of humoral immunity and highlight mechanisms underlying poor vaccine response.