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

Pavlo A Nesterenko; Jami McLaughlin; Brandon L Tsai; Giselle Burton Sojo; Donghui Cheng; Daniel Zhao; Zhiyuan Mao; Nathanael J Bangayan; Matthew B Obusan; Yapeng Su; Rachel H Ng; William Chour; Jingyi Xie; Yan-Ruide Li; Derek Lee; Miyako Noguchi; Camille Carmona; John W Phillips; Jocelyn T Kim; Lili Yang; James R Heath; Paul C Boutros; Owen N Witte

doi:10.1016/j.celrep.2021.110167

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

Cell Rep. 2021 Dec 28;37(13):110167. doi: 10.1016/j.celrep.2021.110167. Epub 2021 Dec 10.

Authors

Pavlo A Nesterenko¹, Jami McLaughlin², Brandon L Tsai³, Giselle Burton Sojo², Donghui Cheng⁴, Daniel Zhao³, Zhiyuan Mao⁵, Nathanael J Bangayan⁵, Matthew B Obusan², Yapeng Su⁶, Rachel H Ng⁷, William Chour⁸, Jingyi Xie⁷, Yan-Ruide Li², Derek Lee², Miyako Noguchi², Camille Carmona⁹, John W Phillips², Jocelyn T Kim⁹, Lili Yang¹⁰, James R Heath¹¹, Paul C Boutros¹², Owen N Witte¹³

Affiliations

¹ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Institute for Systems Biology, Seattle, WA 98109, USA.
⁷ Institute for Systems Biology, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98105, USA.
⁸ Institute for Systems Biology, Seattle, WA 98109, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁹ Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Institute for Systems Biology, Seattle, WA 98109, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

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 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.

Keywords: CD8; COVID-19; SARS-CoV-2; T cells; TCR; antigen; cell therapy; immune response; single-cell; specific.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes / immunology
COVID-19 / immunology
COVID-19 / therapy
Cell Culture Techniques
Coronavirus RNA-Dependent RNA Polymerase / immunology*
Cross Reactions / immunology
Epitopes, T-Lymphocyte / immunology
HLA-A Antigens / immunology
HLA-A2 Antigen / genetics
HLA-A2 Antigen / immunology*
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 / immunology*
SARS-CoV-2 / pathogenicity
Spike Glycoprotein, Coronavirus / immunology

Substances

Epitopes, T-Lymphocyte
HLA-A Antigens
HLA-A*02:01 antigen
HLA-A2 Antigen
Immunodominant Epitopes
RNA, Viral
Receptors, Antigen, T-Cell
Receptors, Antigen, T-Cell, alpha-beta
Spike Glycoprotein, Coronavirus
Coronavirus RNA-Dependent RNA Polymerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding