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

Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires
박대찬Brandon J. DeKoskyOana I. LunguErik L. JohnsonWissam CharabConstantine ChrysostomouDaisuke KurodaAndrew D. EllingtonGregory C. IppolitoJeffrey J. GrayGeorge Georgiou
antibody; B cell; immunology; high-throughput sequencing; computational modeling
Issue Date
Proceedings of the National Academy of Sciences of the United States of America
VOL 113, NO 19-E2645
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 V kappa,lambda-J kappa,lambda 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.; 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-naive 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
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