Improved predictions of antigen presentation and TCR recognition with MixMHCpred2.2 and PRIME2.0 reveal potent SARS-CoV-2 CD8+ T-cell epitopes

• DOI: 10.1016/j.cels.2022.12.002
• Publication Date: 2023-01-05T04:04:48Z
• Authors: David Gfeller; Julien Schmidt; Giancarlo Croce; Philippe Guillaume; Sara Bobisse; Raphael Genolet; Lise Queiroz; Julien Cesbron; Julien Racle; Alexandre Harari
• Keywords: Antigen Presentation; 0303 health sciences; Histology; SARS-CoV-2; Receptors, Antigen, T-Cell; Epitopes, T-Lymphocyte; COVID-19; Cell Biology; CD8-Positive T-Lymphocytes; Ligands; 3. Good health; Pathology and Forensic Medicine; 03 medical and health sciences; HLA Antigens; Report; Humans; Humans; CD8-Positive T-Lymphocytes; Epitopes, T-Lymphocyte; Antigen Presentation; SARS-CoV-2; Ligands; COVID-19; Receptors, Antigen, T-Cell; HLA Antigens; CD8(+) T cell epitopes; HLA-I peptidomics; antigen presentation; computational biology; epitope predictions; immunology; machine learning

The recognition of pathogen or cancer-specific epitopes by CD8+ T cells is crucial for the clearance of infections and the response to cancer immunotherapy. This process requires epitopes to be presented on class I human leukocyte antigen (HLA-I) molecules and recognized by the T-cell receptor (TCR). Machine learning models capturing these two aspects of immune recognition are key to improve epitope predictions. Here, we assembled a high-quality dataset of naturally presented HLA-I ligands and experimentally verified neo-epitopes. We then integrated these data in a refined computational framework to predict antigen presentation (MixMHCpred2.2) and TCR recognition (PRIME2.0). The depth of our training data and the algorithmic developments resulted in improved predictions of HLA-I ligands and neo-epitopes. Prospectively applying our tools to SARS-CoV-2 proteins revealed several epitopes. TCR sequencing identified a monoclonal response in effector/memory CD8+ T cells against one of these epitopes and cross-reactivity with the homologous peptides from other coronaviruses.