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
StatePublished - May 10 2016

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Antigens
Antibodies
B-Lymphocytes
Complementarity Determining Regions
Light
CD20 Antigens
CD27 Antigens
Antibody Binding Sites
Genes
Benchmarking
Structural Models
Population
Antibody Formation
Immunoglobulin M
Amino Acid Sequence
Immunity
Vaccination

ASJC Scopus subject areas

  • General

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Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires. / DeKosky, Brandon J.; Lungu, Oana I.; Park, Daechan; Johnson, Erik L.; Charab, Wissam; Chrysostomou, Constantine; Kuroda, Daisuke; Ellington, Andrew D.; Ippolito, Gregory C.; Gray, Jeffrey J; Georgiou, George.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 19, 10.05.2016, p. E2636-E2645.

Research output: Contribution to journalArticle

DeKosky, BJ, Lungu, OI, Park, D, Johnson, EL, Charab, W, Chrysostomou, C, Kuroda, D, Ellington, AD, Ippolito, GC, Gray, JJ & 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, vol. 113, no. 19, pp. E2636-E2645. https://doi.org/10.1073/pnas.1525510113
DeKosky, Brandon J. ; Lungu, Oana I. ; Park, Daechan ; Johnson, Erik L. ; Charab, Wissam ; Chrysostomou, Constantine ; Kuroda, Daisuke ; Ellington, Andrew D. ; Ippolito, Gregory C. ; Gray, Jeffrey J ; Georgiou, George. / Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 19. pp. E2636-E2645.
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