Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV‐2 S1 Spike Glycoprotein

Cytotoxic T-lymphocytes are critical determinants of SARS-CoV-2 infection severity and long-term immunity. A hallmark of COVID-19 is its highly variable severity and breadth of immune responses between individuals. To address the underlying mechanisms behind this phenomenon we analyzed the proteolytic processing of S1 spike glycoprotein by 10 common allotypes of ER aminopeptidase 1 (ERAP1), an intracellular enzyme that generates antigenic peptides. We utilized a systematic proteomic approach that allows the concurrent analysis of hundreds of trimming reactions. While all ERAP1 allotypes produced optimal ligands for HLA molecules, including known SARS-CoV-2 epitopes, they presented major differences in peptide sequences produced, suggesting allotype-dependent sequence biases. Allotype 10, previously suggested to be enzymatically deficient, was rather found to be functionally distinct from other allotypes. Our findings suggest that common ERAP1 allotypes can be a major source of heterogeneity in antigen processing and through this mechanism contribute to variable immune responses to COVID-19.