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

Gutierrez-Gonzalez, M.; Fahad, A. S.; Ardito, M.; Nanaware, P.; Lu, L.; Normandin, E.; Madan, B.; Tivin, J.; Coates, E.; Henry, A. R.; Laboune, F.; Graham, B. S.; Douek, D. C.; Ledgerwood, J. E.; Mascola, J. R.; Martin, W. D.; Stern, L.; De Groot, A. S.; DeKosky, B. J.

doi:10.1101/2021.01.15.426750

bioRxiv · 10.1101/2021.01.15.426750

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

Gutierrez-Gonzalez, M.·Fahad, A. S.·Ardito, M.·Nanaware, P.·Lu, L.·Normandin, E.·Madan, B.·Tivin, J.·Coates, E.·Henry, A. R.·Laboune, F.·Graham, B. S.·Douek, D. C.·Ledgerwood, J. E.·Mascola, J. R.·Martin, W. D.·Stern, L.·De Groot, A. S.·DeKosky, B. J.

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Abstract

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. HighlightsO_LIAntibody somatic hypermutation selectively removes MHC-II peptide epitopes from B cell receptors. C_LIO_LIAntibodies with lower MHC-II epitope content show evidence of greater T cell help, including class-switching. C_LIO_LIMHC-II peptide epitope removal from a BCR is linked to long-term antibody secretion in serum. C_LIO_LIMHC-II genotype provides a personalized selection pressure on human antibody development. C_LI

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Gutierrez-Gonzalez, M., Fahad, A. S., Ardito, M., Nanaware, P., Lu, L., Normandin, E., Madan, B., Tivin, J., Coates, E., Henry, A. R., Laboune, F., Graham, B. S., Douek, D. C., Ledgerwood, J. E., Mascola, J. R., Martin, W. D., Stern, L., De Groot, A. S., DeKosky, B. J.. 2021-01-17. Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes. https://doi.org/10.1101/2021.01.15.426750

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