HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses

• Published in: Cell reports (Cambridge) Vol. 37; no. 13; p. 110167
• Main Authors: Nesterenko, Pavlo A., McLaughlin, Jami, Tsai, Brandon L., Burton Sojo, Giselle, Cheng, Donghui, Zhao, Daniel, Mao, Zhiyuan, Bangayan, Nathanael J., Obusan, Matthew B., Su, Yapeng, Ng, Rachel H., Chour, William, Xie, Jingyi, Li, Yan-Ruide, Lee, Derek, Noguchi, Miyako, Carmona, Camille, Phillips, John W., Kim, Jocelyn T., Yang, Lili, Heath, James R., Boutros, Paul C., Witte, Owen N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.12.2021; The Author(s)
• Subjects: antigen; CD8; CD8-Positive T-Lymphocytes - immunology; Cell Culture Techniques; cell therapy; Coronavirus RNA-Dependent RNA Polymerase - immunology; COVID-19; COVID-19 - immunology; COVID-19 - therapy; Cross Reactions - immunology; Epitopes, T-Lymphocyte - immunology; HLA-A Antigens - immunology; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; Humans; immune response; Immunodominant Epitopes - immunology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - virology; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; RNA, Viral - genetics; SARS-CoV-2; SARS-CoV-2 - immunology; SARS-CoV-2 - pathogenicity; single-cell; specific; Spike Glycoprotein, Coronavirus - immunology; T cells; TCR; COVID-19; SARS-CoV-2; TCR; immune response; CD8; cell therapy; single-cell; antigen; T cells; specific
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110167

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 TCRαβ 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 TCRαβ 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. [Display omitted] •The RNA-dependent RNA-polymerase is highly conserved among human coronaviruses•CD8+ T cells from unexposed donors recognize SARS-CoV-2 polymerase epitopes•TCR engineered T cells kill target cell lines that express the polymerase•Polymerase-reactive TCRs cross-react with seasonal coronaviruses 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.