Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):E2622-9. doi: 10.1073/pnas.1403278111. Epub 2014 Jun 9.


Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (VH)-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in VH gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use VH genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential VH gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.

Keywords: development; immunomics; principal component analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology*
  • Female
  • High-Throughput Nucleotide Sequencing
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology*
  • Mice


  • Complementarity Determining Regions
  • Immunoglobulin Heavy Chains

Associated data

  • BioProject/PRJNA248676