Complex Antigens Drive Permissive Clonal Selection in Germinal Centers

Immunity. 2016 Mar 15;44(3):542-552. doi: 10.1016/j.immuni.2016.02.010. Epub 2016 Mar 3.

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.

Keywords: B cell repertoire; clonal selection; germinal center; influenza hemagglutinin; protective antigen of B. anthracis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Affinity / genetics
  • Antibody Diversity
  • Antigens, Bacterial / immunology
  • B-Lymphocytes / physiology*
  • Bacterial Toxins / immunology
  • Cells, Cultured
  • Clonal Selection, Antigen-Mediated*
  • Female
  • Germinal Center / immunology*
  • Hemagglutinins, Viral / immunology
  • Humans
  • Immunity, Humoral
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Orthomyxoviridae / metabolism
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / metabolism*
  • Single-Domain Antibodies / genetics

Substances

  • Antigens, Bacterial
  • Bacterial Toxins
  • Hemagglutinins, Viral
  • Receptors, Antigen, B-Cell
  • Single-Domain Antibodies
  • anthrax toxin