title: Complex Antigens Drive Permissive Clonal Selection in Germinal Centers.
abstract: Germinal center (GC) B cells evolve toward increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten-specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens-Bacillus anthracis protective antigen and influenza hemagglutinin-in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naive B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early "winners" were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection.
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kuraoka
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Schmidt
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nojima
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; Department of Mathematics and Statistics, Boston University, Boston, MA 02118, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA; Human Vaccine Institute, Duke University, Durham, NC 27710, USA. Electronic address: ghkelsoe@duke.edu.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000235:genetics; D000916:Antibody Diversity; D000942:Antigens, Bacterial / Q000276:immunology; D001402:B-Lymphocytes / Q000502:physiology*; D001427:Bacterial Toxins / Q000276:immunology; D002478:Cells, Cultured; D060966:Clonal Selection, Antigen-Mediated; D005260:Female; D018858:Germinal Center / Q000276:immunology*; D006389:Hemagglutinins, Viral / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D061905:Single-Domain Antibodies / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D006389:Hemagglutinins, Viral; D011947:Receptors, Antigen, B-Cell; D061905:Single-Domain Antibodies; C030325:anthrax toxin
keywords: B cell repertoire; clonal selection; germinal center; influenza hemagglutinin; protective antigen of B. anthracis