Recombinant adenoviruses have been used as vehicles for gene therapy as well as vaccination against infectious diseases and cancer. Efficient activation of host B cell response to adenoviral vectors that leads to the generation of protective, neutralizing Ab, represents a major barrier for gene therapy, but an attractive feature for vaccine development. What regulate (s) potent B cell response to adenoviral vectors remains incompletely defined. In this study, we showed that type I IFNs induced upon adenoviral infection are critical for multiple stages of adaptive B cell response to adenovirus including early B cell activation, germinal center formation, Ig isotype switching as well as plasma cell differentiation. We further demonstrated that although type I IFN signaling on dendritic cells was important for the production of virus-specific IgM, the generation of protective neutralizing Ab critically depended on type I IFN signaling on both CD4 T and B cells. The results may suggest potential strategies for improving adenovirus-mediated gene therapy in vivo and/or the design of effective vaccines for cancer and infectious diseases.

Replication-defective adenoviral vectors have been used widely in gene therapy applications due to their high efficiency of transduction into a wide variety of nondividing cells in vivo (1). However, significant problems of attendant host innate and adaptive immune responses have limited the use of adenoviral vectors for gene therapy because of the concerns for their safety and efficacy in vivo (1, 2). Interestingly, the inherent immunogenicity of adenoviral vectors has led to their development as potential vaccine vehicles for infectious diseases such as HIV and malaria, and cancer (3, 4). Among host immune responses, efficient generation of neutralizing Abs to the vectors and transgenes represents a major barrier for gene therapy (5, 6, 7), but a desirable feature for vaccine development (3, 4). Although studies have shown that Ab response to adenoviral vectors is CD4 Th cell dependent (6, 8), it remains to be defined whether other signals, particularly innate immune cytokines, also contribute to potent humoral immune response upon adenoviral infection. Thus, further elucidation of these potential signals required for efficient B cell response may help us design effective vaccines as well as strategies to allow repeated administration of the vector for gene therapy in vivo.