A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization

Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human Immunodeficiency Virus Gag-Pol polyprotein. Author Summary: Major Histocompatibility Complex (MHC) class I molecules bind to protein fragments (peptides) within the cell and present these fragments at the cell surface, thus providing a snapshot of the cell contents that can subsequently be used to trigger an immune response. Only a fraction of the potentially billions of peptides inside a cell are selected for presentation, and the process is optimized to select for peptides that form a stable complex with MHC class I. The mechanisms of the optimization process are important for predicting the efficacy of an immune response and for designing effective vaccines, yet are still not well-understood. In this article we present a dynamical systems model of peptide optimization by MHC class I. We show that peptide optimization can be quantified and mechanistically explained by a peptide filtering relation, which relates cell surface abundance to peptide supply, peptide unbinding and interactions with the chaperone molecule tapasin. The filtering relation also accounts for differences in optimization across MHC class I alleles. Finally, we show how the filtering relation can be used to quantify the cell-surface presentation of virus-derived peptides for immune system surveillance.