title: Activation and negative selection of functionally distinct subsets of antibody-secreting cells by influenza hemagglutinin as a viral and a neo-self antigen.
abstract: We have compared transgenic mice that express the influenza virus PR8 hemagglutinin (PR8 HA) as a membrane-bound neo-self antigen (HA104 mice) with nontransgenic (non-Tg) mice for their ability to generate HA-specific B cell responses after primary immunization with PR8 virus. HA-specific, IgM-secreting B cells were induced with similar frequencies in HA104 and non-Tg mice. In addition, a B cell clonotype (C4) that is characteristic of anti-HA immune responses of BALB/c mice was identified among HA-specific IgM hybridomas from HA104 mice. A subset of HA-specific, IgG-secreting B cells that arises rapidly after primary virus immunization in non-Tg mice, however, was substantially reduced in HA104 mice. Likewise, a B cell clonotype (C12) that dominates HA-specific IgG hybridomas generated after primary immunization of non-Tg mice was present at greatly reduced frequencies among hybridomas from HA104 mice. Because HA-specific, IgG-secreting B cells were generated by HA104 mice in response to a mutant HA containing an amino acid interchange in a B cell antigenic site, we conclude that these PR8 HA-specific, IgG-secreting B cells are negatively selected in HA104 mice as a result of their specificity for the neo-self PR8 HA. The findings demonstrate that HA-specific B cells that display distinct phenotypic potentials in non-Tg mice also differ in their susceptibility to negative selection from the primary B cell repertoire of HA104 mice: a subset of B cells that undergo rapid differentiation to become HA-specific IgG antibody-secreting cells (ASC) after activation in non-Tg mice is negatively selected in HA104 mice. By contrast, a subset that gives rise to HA-specific, IgM-secreting ASC persists in the primary repertoire of HA104 mice and can be activated by virus immunization.
authors.affiliation: Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Caton
authors.forename: J R
authors.initials: JR
authors.lastname: Swartzentruber
authors.forename: A L
authors.initials: AL
authors.lastname: Kuhl
authors.forename: S R
authors.initials: SR
authors.lastname: Carding
authors.forename: S E
authors.initials: SE
authors.lastname: Stark
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001483:Base Sequence; D002999:Clone Cells; D004797:Enzyme-Linked Immunosorbent Assay; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006825:Hybridomas; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D000956:Antigens, Viral; D001324:Autoantigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region