Identification And Characterization Of An Immunodominant Sars-Cov-2-Specific Cd8 T Cell Response

Background Global efforts are ongoing to develop vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease (COVID-19). While there is accumulating information on antibody responses against SARS-CoV-2, less is known about CD8 T-cell recognized SARS-CoV-2 epitopes and the functional state of SARS-CoV-2-specific CD8 T cells. Methods We analysed samples from 18 patients with ongoing severe and critical COVID-19 disease for CD8 T-cell recognition of 500 peptide human leukocyte antigen (HLA) class I complexes, restricted by 10 common HLA alleles. In addition we carried out an in-depth characterisation of the functional state of identified SARS-CoV-2-specific CD8 T cell responses based on peptide stimulation assays, ex vivo flow cytometry and transcriptome analysis. Results Several epitopes derived from the open reading frame 1ab polyprotein (ORF1ab) were identified, including an immunodominant epitope restricted by HLA-A*01:01.The immunodominance was further supported by high T cell receptor (TCR) diversity within the CD8 T cells specific for this epitope. In-depth characterisation the immundominant SARS-CoV-2-specific CD8 T cell response revealed a regulated activation program that maintains CD8 T cell survival while halting their effector function and migratory capacity. Conclusions The ORF1ab, that was found to be the source of an immunodminant SARS-Cov-2-specific CD8 T cell epitope, is not included in the majority of vaccine candidates in development, which may influence their clinical activity. Furthermore, these data may be a cautious indication that SARS-CoV-2 specific CD8 T cells – unlike CD4 T cells – are less likely to contribute to the immunopathology observed in severely and critically ill COVID-19 patients. Ethics Approval The samples from both COVID-19 patients were collected in accordance with the Declaration of Helsinki after approval by the institutional review boards. Consent Each participant signed informed consent.