Shield or Showcase: Unraveling How BCR Binding Shapes MHCII Peptide Presentation for CD4+ T Cell Activation 2256684

Abstract Introduction Effective cooperation between B cells and CD4+ T cells is central to durable antibody responses. This interaction is mediated by B cells presenting MHC class II (MHCII) peptides to activate CD4+ T cells. However, how B cells select the optimal MHCII peptide for display remains unresolved. Two competing models seek to explain this process. Model 1 suggests the B cell receptor (BCR) displays MHCII peptides derived broadly from the internalized immunogen. Model 2 states that BCR binding protects its contact region, thereby selecting MHCII peptides from the shielded region. Resolving this mechanistic question is fundamental to faster immunogen design and improved vaccine efficacy. Methods We developed a computational framework integrating structural, proteolytic, and immunogenetic features. Antigen—antibody complexes were analyzed using modeling tools to map BCR—epitope contact sites. Patient-specific MHCII alleles and immunogen sequences were evaluated with NetMHCIIpan to predict high-affinity candidate MHCII peptides. Custom Python pipelines are being developed to model endolysosomal protease cleavage and assess antibody influence on peptide stability. Results Preliminary analysis of spatial proximity of candidate MHCII peptides to the antibody interface and modelling of MHCII—peptide interactions by molecular docking indicates a possible co-relation between BCR proximity and predicted MHCII peptide affinity. Assessment of how antibody engagement influences peptide degradation is ongoing. Altogether, these results will develop a user-accessible tool that can predict optimal MHCII peptides within vaccine immunogens that elicit greater antibody responses. Conclusion This framework provides a powerful lens to visualize BCR engagement with the MHCII peptides using computational modelling. Insights from these studies will advance understanding of T—B cell cooperation and guide rational design of next-generation vaccines that more effectively recruit CD4+ T cell help and drive durable antibody responses Funding Source LOS ALAMOS NATIONAL LABORATORY Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)