Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes
Ahmed S. Fahad,
Amy R Henry,
Barney S Graham,
Daniel C. Douek,
Julie E. Ledgerwood,
John R Mascola,
William D. Martin,
Annie S De Groot,
Brandon J. DeKosky
Posted 17 Jan 2021
bioRxiv DOI: 10.1101/2021.01.15.426750
Posted 17 Jan 2021
Human antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody development in vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of class-switched sequences and serum proteomic data revealed that MHC-II epitope deletion is associated with antibody class switching and long-term secretion into serum. These data suggest that the MHC-II peptide epitope content of a BCR is an important determinant of antibody maturation that shapes the composition and durability of humoral immunity.
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