Background: The magnitude of CD8+ T lymphocyte responses to infection are a function of a multitude of factors that include the available naïve T cell repertoire combined with the context and duration of peptide presentation by major histocompatibility complex (MHC) molecules. Measurement of these factors therefore allows an assessment of their contribution to – and ultimately a chance to model and predict – immunogenicity.
Methodologies: Here, we have used a combination of discovery and targeted mass spectrometry to assess the virus-derived immunopeptidome following different models of virus infection and antigen presentation, combined with measurements of peptide-MHC binding affinity and the elicited CD8 T cell response of each peptide.
Results: These data highlight the diversity in viral peptide-MHC display following infection and the dramatic changes in absolute abundance and kinetics, as well as modulation of the presentation hierarchy in direct- versus cross-presentation pathways. Screening of each peptide for immunogenicity in multiple virus-infected mice revealed a wide range of immunogenicities. Together, these data have helped to train mathematical models that delineate the relative importance of these factors and provide a critical step towards predicting immunogenicity.
Conclusions: This study highlights how high quality quantitative proteomics and peptidomics data are pivotal in unraveling the complex ecosystem of immune responses to viruses and provides the foundation for the rational design of interventional and therapeutic strategies for viruses that remain a serious threat to humankind.