PT  - JOURNAL ARTICLE
AU  - Matias Gutiérrez-González
AU  - Ahmed S. Fahad
AU  - Matt Ardito
AU  - Padma Nanaware
AU  - Liying Lu
AU  - Erica Normandin
AU  - Bharat Madan
AU  - Jacob Tivin
AU  - Emily Coates
AU  - Amy R. Henry
AU  - Farida Laboune
AU  - Barney S. Graham
AU  - Daniel C. Douek
AU  - Julie E. Ledgerwood
AU  - John R. Mascola
AU  - William D. Martin
AU  - Lawrence J. Stern
AU  - Annie S. De Groot
AU  - Brandon J. DeKosky
TI  - Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes
AID  - 10.1101/2021.01.15.426750
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.15.426750
4099  - http://biorxiv.org/content/early/2021/01/17/2021.01.15.426750.short
4100  - http://biorxiv.org/content/early/2021/01/17/2021.01.15.426750.full
AB  - 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.HighlightsAntibody somatic hypermutation selectively removes MHC-II peptide epitopes from B cell receptors.Antibodies with lower MHC-II epitope content show evidence of greater T cell help, including class-switching.MHC-II peptide epitope removal from a BCR is linked to long-term antibody secretion in serum.MHC-II genotype provides a personalized selection pressure on human antibody development.Competing Interest StatementM.A., J.T., W.M., and A.S.G. are employees of Epivax, Inc., which commercializes the EpiMatrix prediction tool.