Martin, W. D. | bioRxiv Science

bioRxiv2021

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

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

immunology↗

bioRxiv2019

Coxiella burnetii epitope-specific T-cell responses in chronic Q fever patients

Infection with Coxiella burnetii, the causative agent of Q fever, can result in life-threatening persistent infection. Reactogenicity hinders worldwide implementation of the only licensed human Q fever vaccine. We previously demonstrated long-lived immunoreactivity in individuals with past symptomatic and asymptomatic Coxiella infection (convalescents) to promiscuous HLA-class II C. burnetii epitopes, providing the basis for a novel T-cell-targeted subunit vaccine. Here we investigated in a cohort of 22 individuals with persistent infection (chronic Q fever) whether they recognize the same set of epitopes, or distinct epitopes that could be candidates for a therapeutic vaccine or aid in the diagnosis of persistent infection.\n\nIndividuals with chronic Q fever showed strong class II epitope-specific cultured ELISpot responses largely overlapping with the peptide repertoire identified previously for convalescents. Five additional peptides were recognized more frequently by chronic subjects, but there was no combination of epitopes uniquely recognized by or non-reactive in chronic Q fever subjects. Consistent with more recent/prolonged exposure, we found, however, stronger direct ex vivo responses to whole-cell C. burnetii and individual peptides in direct ELISpot than in convalescents.\n\nIn conclusion, we have validated and expanded a previously published set candidate epitopes for a novel T-cell targeted subunit Q fever vaccine in the context of chronic Q fever patients and demonstrated that they successfully mounted a T-cell response comparable to that of convalescents. Finally, we demonstrate that individuals treated for chronic Q fever mount a broader ex vivo response to class II epitopes than convalescents, which could be explored for diagnostic purposes.

immunology↗