Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

Brandon J. DeKosky, Oana I. Lungu, Daechan Park, Erik L. Johnson, Wissam Charab, Constantine Chrysostomou, Daisuke Kuroda, Andrew D. Ellington, Gregory C. Ippolito, Jeffrey J Gray, George Georgiou

Research output: Contribution to journalArticle

Abstract

Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy-and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19+CD20+CD27? IgM-naïve B cells, >120,000 antibody clusters from CD19+CD20+CD27+ antigen-experienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-Accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λJκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease.

Original languageEnglish (US)
Pages (from-to)E2636-E2645
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number19
DOIs
Publication statusPublished - May 10 2016

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this