ABSTRACT
Cross-reactivity and direct killing of target cells remain underexplored for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA polymerase (RdRp/NSP12) as highly conserved, likely due to its critical role in the virus life cycle. We perform single-cell TCRαß sequencing in human leukocyte antigen (HLA)-A∗02:01-restricted, RdRp-specific T cells from SARS-CoV-2-unexposed individuals. Human T cells expressing these TCRαß constructs kill target cell lines engineered to express full-length RdRp. Three TCR constructs recognize homologous epitopes from common cold coronaviruses, indicating CD8+ T cells can recognize evolutionarily diverse coronaviruses. Analysis of individual TCR clones may help define vaccine epitopes that can induce long-term immunity against SARS-CoV-2 and other coronaviruses.
Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/immunology , HLA-A2 Antigen/immunology , SARS-CoV-2/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/therapy , Cell Culture Techniques , Cross Reactions/immunology , Epitopes, T-Lymphocyte/immunology , HLA-A Antigens/immunology , HLA-A2 Antigen/genetics , Humans , Immunodominant Epitopes/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , RNA, Viral/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
Nesterenko et al. identify T cell responses with potential to confer long term immunity against SARS-CoV-2. The machinery responsible for replicating the viral genome is highly conserved and as shown by Nesterenko et al. can be effectively targeted by CD8+ T cells.