The plasmid pCR-script Amp SK(+)-Cotton rat IL-6 was kindly provided by Dr. of B cell and antibody responses after immunization in the presence of inhibitory MeV-specific IgG. The strong stimulatory action of type I interferon is due to the fact that type I interferon uses not only the interferon receptor but also CD21 as a functional receptor for B cell activation. Author Summary Maternal antibodies provide protection against infection with pathogens early in life but also interfere with vaccination. This interference is caused by a vaccine/maternal antibody complex which links the B cell receptor to the inhibitory CD32 molecule. Here, we show that this cross-link results in impaired B cell activation and proliferation which is correlated with diminished antibody responses. We also found that induction of large amounts of type I interferon restores the neutralizing antibody response in the presence of maternal antibodies. The best induction of type I interferon was accomplished by a combination of known activators of interferon secretion (a combination of TLR-3 and TLR-9 agonists). The strong stimulation by interferon is due to the previously unappreciated role of CD21 as functional receptor for interferon alpha. Our findings demonstrate that the dual receptor usage of type I interferon receptor and CD21 is crucial for B cell activation in the presence of maternal antibodies. This study suggests that measles vaccine, and potentially other vaccines, may induce optimal antibody responses when they are reconstituted with TLR-3 and TLR-9 agonists and thus these agonists may have great potential for clinical use. Introduction A fundamental unresolved issue in vaccinology is the inhibition of vaccination against infectious diseases of humans [1], [2],[3], [4], [5], [6], [7] and animals [8], [9], [10], [11], [12], [13], [14], [15], [16], [17] by maternal antibodies. Studies in patients as well as experiments in animal models testing adjuvants and vaccine vectors have shown that maternal antibodies do not inhibit T cell responses [18], [19], [20], [14]. However, if protection (at least partially) depends on the B cell response and production of neutralizing antibodies (as it does for measles virus and many other pathogens), vaccination regularly fails. Worldwide, close to 200,000 children die of measles virus every year. During their first year of life, children are protected by neutralizing maternal antibodies against MeV infection. Over time, these antibody UNBS5162 titers wane and eventually do not protect against wildtype virus infection (for review [21]). However, even these low non-protective antibody titers inhibit the generation of MeV-specific antibodies (both neutralizing and non-neutralizing antibodies) but not the development of a MeV-specific T cell response [18]. As neutralizing antibodies but not T cells protect against infection [19], [22], [23], these children are susceptible to MeV infection. We have used UNBS5162 the cotton rat (Sigmodon hispidus) model of measles vaccination to analyze the inhibitory mechanism of maternal antibodies because the cotton rat is the only rodent LDH-B antibody in which measles virus after intranasal inoculation replicates in the respiratory tract and lymphoid organs [24]. In this animal model, we have been able to demonstrate that both natural maternal MeV-specific IgG antibodies, as well as passively transferred human and mouse MeV-specific IgG are able to inhibit the generation of MeV-specific antibodies (both neutralizing and non-neutralizing antibodies) after immunization [19], [25], [26]. B cell inhibition is due to cross-linking of the B cell receptors (BCR) and Fc receptors IIB (FcRIIB) by a complex formed by maternal IgG and the UNBS5162 MeV vaccine [26]. This inhibitory effect can be partially overcome by activation of B cells through cross-linking BCR and complement receptor 2 (CR-2/CD21) with a complex of MeV vaccine, MeV-specific IgM and complement protein C3d [26]. Two viral vector systems (vesicular stomatitis virus (VSV) and Newcastle Disease virus (NDV)) which express UNBS5162 measles virus hemagglutinin (H) can induce H specific neutralizing antibodies after vaccination in the presence of inhibitory MeV-specific IgG. In contrast to measles virus, both VSV [27] as well as NDV induce type I interferon [28]. For NDV we have shown that its ability to induce neutralizing antibodies correlates with its ability to induce type I interferon in cotton rat plasmacytoid dendritic cells, and in cotton rat lung tissue [28]. In vitro, neutralization of IFN abrogates stimulation of B cell responses by NDV. Viruses induce type I interferon through viral nucleic acids which.