This project aims to better define the role of T cells in antibody production (‘T-B cooperation’). T follicular helper cells are required in most cases to promote differentiation of naive B cells into memory or plasma (antibody-secreting) B cells. T cells stimulate this differentiation of B cells upon encountering immunogenic MHC Class II peptides presented by B cells; these peptides are derived from proteins bound to and internalized by naive B cell antibodies (B cell receptors). While it is generally assumed that these peptides could be produced from any region of the internalized protein, this project aims to better understand whether BCR binding restricts generation of MHC Class II peptides. Specifically, we will assess whether these peptides are more likely to be in close proximity to BCR epitopes, and we will also consider access by endolysosomal enzymes required to cleave these peptides from the internalized protein. To address this question, we request the following data from UK Biobank: imputed HLA alleles (Category 100035), seropositivity assay values for infectious diseases (Category 51428), and seropositivity for SARS-CoV-2 vaccination (Category 997) and vaccination/infection (Category 998). We will determine whether antibodies titers are associated with presence of HLA allele-binding peptides in close proximity to known antibody binding sites on the antigen protein. We intend to do similar analyses using additional data sources. Ultimately, we plan to publish our findings and also incorporate them into a vaccine design tool made available to the public optimizing immunogen protein sequences for MHC Class II peptide generation in the context of BCR binding.
