DynOMIS · Dynamic Origins of MHC class I Selector function

Dynamic Origins of MHC class I Selector function

Our health and wellbeing is constantly under threat from infectious pathogens, as well as the ‘enemy-within’ in the form of malignantly transformed cells. Evolution has driven the development of adaptive immunity to identify and eliminate transformed or infected cells. Immune detection requires a constant turnover of cellular proteins to peptides, which are presented at the cell surface by major histocompatibility complex class I molecules (MHC-I) and scanned by cytotoxic T lymphocytes (CTL). A sophisticated system of self–nonself discrimination ensures that CTL only unleash their cytotoxic apparatus when they encounter peptides derived from foreign microbes, or from tumour-associated proteins, hereby ensuring that only non-healthy cells are eliminated. The peptide presenting function of MHC-I at the cell surface is the result of an equally, if not more important, peptide selecting function in the early secretory pathway. MHC-I molecules acquire peptide cargo soon after their synthesis and assembly with β2-microglobulin in the endoplasmic reticulum (ER), while they are part of a multi-subunit machinery called the peptide-loading complex. Even minor changes in the primary sequence of MHC-I, which do not affect their peptide presenting function, can lead to large differences in their peptide selecting function. Importantly, this cannot be understood by analysing the structures of MHC-I allomorphs in complex with different peptides provided by X-ray crystallography as they are virtually identical. DynOMIS is the first attempt to link a quantitative cellular level description of a fundamental biological process and its atomistic realization. The proposed methodology integrates computational systems modelling, state-of-the-art molecular dynamics and free energy calculations with information from cellular, biochemical and advanced Nuclear Magnetic Resonance (NMR) experiments in a highly innovative way. Deep understanding of the exact mechanisms that drive peptide selection by MHC-I will enhance the ability to predict immunoprotective epitopes in infections and cancer. This will in turn pave the way for the development of more effective CTL-targeted vaccines and biomarkers to stratify patients’ suitability for immunotherapy, such as checkpoint inhibition in cancer.

Data: CORDIS, © European Union