Defining the role of shared T-cell receptor clonotypes in SARS-CoV-2 infection

T cells are a major component of adaptive immune response, continuously screening lymphoid tissues for antigen peptides presented by major histocompatibility complex (peptide/MHC or pMHC)3. These antigen peptides are recognized by T-cell receptors (TCRs). Thymocytes with a low-affinity TCRs mature into T cells and enter the lymphoid organs, where they are exposed to foreign antigen peptides by MHC molecules from antigen-presenting cells including macrophages, dendritic cells, and B-cells, during infection. When the T-cell receptors bind to antigenic peptide, T-cells are activated and undergo clonal expansion, resulting in immune response. CD8+ T cells play an important for immune response and viral clearing, but their role in protection and pathogenesis of SARS-CoV-2 remains poorly understood4. In addition to extensively studied spike protein, open reading frame 3a (ORF3a), a highly conserved protein within the Betacoronavirus subgenus, has been considered as a potential target for vaccines or therapeutics, with deletion of ORF3a resulting in decreased viral titer and morbidity. We have identified shared CD8+ T cell clonotypes responding to a ORF3a in COVID-19 infections.  Importantly, shared clonotypes in severe COVID-19 infections provides a target for development of novel antiviral immunotherapies. The aim of this project is to analyse shared TCR clonotypes in ORF3a recognition and provide structural basis for the recognition of ORF3a-pMHC complex by T-cell receptors.