Fast-Dissociating High-Supply Peptides as Contributors to MHC-I Antigen Presentation

The major histocompatibility complex class I (MHC-I) immunopeptidome is dynamic and determined by numerous biochemical and cellular features. Computational tools to predict peptide-MHC-I binding focus on the affinity of a specific peptide-MHC interaction; separate tools predict complex stability or presentation. Methods used to define the immunopeptidome may preferentially recover stable complexes, and presentation predictors trained on those data may inherit that bias. However, peptides that dissociate rapidly but are generated at high rates could reach surface densities sufficient for CD8⁺ T cell recognition. Here, we examine evidence relevant to these fast-dissociating high-supply (FDHS) peptides and develop a two-axis model, whereby peptide supply is considered alongside stability. We examine how defective ribosomal products and ribosome-associated quality control supply peptides for MHC-I loading. We set out the limits of tapasin-mediated editing and compare the model with the binding, stability and presentation predictors now in use. Experiments have linked peptide abundance and complex stability to relative presentation, but the extent of compensation for endogenous FDHS peptides remains to be quantified. We present experimental systems to test the magnitude and limits of this compensation, specifying the key measurements. We also propose that FDHS ligands generated under tumour-specific translational stress could be less constrained by central tolerance if their presentation is insufficient during thymic selection. We believe this model has implications for understanding the broader immunopeptidome, how it contributes to innate and adaptive immunity, and designing better immunotherapies.