title: Synergistic induction of interferon α through TLR-3 and TLR-9 agonists identifies CD21 as interferon α receptor for the B cell response.
abstract: Maternal antibodies inhibit seroconversion and the generation of measles virus (MeV)-specific antibodies (both neutralizing and non-neutralizing antibodies) after vaccination whereas T cell responses are usually unaffected. The lack of seroconversion leaves individuals susceptible to vaccine-preventable infections. Inhibition of antibody secretion is due to the inhibition of B cells through a cross-link of the B cell receptor with the inhibitory FcγIIB receptor (CD32) by maternal antibody/vaccine complexes. Here, we demonstrate that a combination of TLR-3 and TLR-9 agonists induces synergistically higher levels of type I interferon in vitro and in vivo than either agonist alone. The synergistic action of TLR-3 and TLR-9 agonists is based on a feedback loop through the interferon receptor. Finally, we have identified CD21 as a potential receptor for interferon α on B cells which contributes to interferon α-mediated activation of B cells in the presence of maternal antibodies. The combination leads to complete restoration 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.
authors.affiliation: Department of Veterinary Biosciences, Ohio State University, Columbus, OH, USA.
authors.forename: Dhohyung
authors.initials: D
authors.lastname: Kim
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007114:Immunization; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008459:Measles virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000378:metabolism; D011817:Rabbits; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017384:Sequence Deletion; D016205:Sigmodontinae; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology; D014709:Vero Cells
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C526902:CpG ODN 2216; D007155:Immunologic Factors; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D017464:Receptors, Complement 3d; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D053633:Receptor, Interferon alpha-beta