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

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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
StatePublished - May 10 2016

ASJC Scopus subject areas

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    DeKosky, B. J., Lungu, O. I., Park, D., Johnson, E. L., Charab, W., Chrysostomou, C., Kuroda, D., Ellington, A. D., Ippolito, G. C., Gray, J. J., & Georgiou, G. (2016). Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires. Proceedings of the National Academy of Sciences of the United States of America, 113(19), E2636-E2645. https://doi.org/10.1073/pnas.1525510113