Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes

Summary 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. Highlights Antibody 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.