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

Nesterenko, Pavlo A. and McLaughlin, Jami and Tsai, Brandon L. and Burton Sojo, Giselle and Cheng, Donghui and Zhao, Daniel and Mao, Zhiyuan and Bangayan, Nathanael J. and Obusan, Matthew B. and Su, Yapeng and Ng, Rachel H. and Chour, William and Xie, Jingyi and Li, Yan-Ruide and Lee, Derek and Noguchi, Miyako and Carmona, Camille and Phillips, John W. and Kim, Jocelyn T. and Yang, Lili and Heath, James R. and Boutros, Paul C. and Witte, Owen N. (2021) HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses. Cell Reports, 37 (13). Art. No. 110167. ISSN 2211-1247. PMCID PMC8660260. doi:10.1016/j.celrep.2021.110167.

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[img] MS Excel (Table S1. Summary of reactive TCR clones and cognate epitopes, related to Figure 2) - Supplemental Material
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[img] MS Excel (Table S2. Nucleotide sequence of TCR clones that have been validated in PBMCs, related to Figure 2) - Supplemental Material
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[img] MS Excel (Table S3. Specificity patterns determined from grouping RdRp-specific TCRαβ clones with the MIRA dataset by GLIPH2 analysis, related to Figure 3) - Supplemental Material
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[img] MS Excel (Table S4. Acknowledgment of SARS-CoV-2 sequencing sources, related to Figure 1) - Supplemental Material
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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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Nesterenko, Pavlo A.0000-0001-9841-8170
Tsai, Brandon L.0000-0002-7372-3504
Zhao, Daniel0000-0001-7779-5452
Mao, Zhiyuan0000-0002-5536-4691
Obusan, Matthew B.0000-0002-9579-2308
Su, Yapeng0000-0002-6305-8467
Ng, Rachel H.0000-0003-3692-8524
Chour, William0000-0003-1817-0123
Noguchi, Miyako0000-0003-0909-7358
Carmona, Camille0000-0001-7040-5773
Kim, Jocelyn T.0000-0001-8723-8190
Heath, James R.0000-0001-5356-4385
Boutros, Paul C.0000-0003-0553-7520
Witte, Owen N.0000-0003-4461-4533
Additional Information:© 2021 The Author(s). This is an open access article under the CC BY license ( Received 11 August 2021, Revised 15 October 2021, Accepted 2 December 2021, Available online 10 December 2021. We thank Michael T. Bethune for providing advice throughout this project, as well as providing the Jurkat-CD8 cells while at the laboratory of David Baltimore (Caltech). The NFAT reporter was a gift from Christopher S. Seet (UCLA) and the laboratory of David Baltimore (Caltech). We thank Caius Radu and Ting-Ting Wu (UCLA) for critical reading of the manuscript. The UCLA Technology Center for Genomics and Bioinformatics constructed single-cell human TCR libraries and performed TCR sequencing. Funding: National Cancer Institute grants U01 CA233074 (O.N.W.) and U24 CA248265 (P.C.B.); Parker Institute for Cancer Immunotherapy grant (O.N.W. and J.R.H.); UCLA Broad Stem Cell Research Center (O.N.W.); USHHS Ruth L. Kirschstein Institutional National Research Service Award T32 CA009056 (P.A.N.); Broad Stem Cell Research Center (BSCRC) predoctoral fellowship (Z.M.); The Jeff and Liesl Wilke Foundation (J.R.H.); The Washington State Andy Hill CARE Fund (J.R.H.); The Biomedical Advanced Research and Development Authority HHSO10201600031C (J.R.H.); UCLA W. M. Keck Foundation COVID-19 Research Award Program (O.N.W.). Data and code availability: Reactive TCR alpha/beta nucleotide sequences are provided in this paper. We have not created any original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Author contributions: Conceptualization, P.A.N. and O.N.W.; supervision, P.A.N., O.N.W., J.M., J.T.K., J.R.H., P.C.B., and J.W.P.; methodology, M.T.B., P.A.N., P.C.B., J.R.H., W.C., Y.S., L.Y., Z.M., N.J.B., Y.L., D.L., and J.T.K.; investigation, G.B.S., J.M., P.A.N., J.X., R.N., B.L.T., D.C., C.C., and M.N.; funding acquisition, J.W.P., P.C.B., and O.N.W.; software, M.B.O., B.L.T., R.N., and D.Z.; resources, J.X., W.C., and Y.L.; visualization, M.B.O., P.A.N., B.L.T., D.Z., and R.N.; project administration, P.A.N., J.M., and O.N.W.; writing – original draft, review & editing, P.A.N., O.N.W., and J.W.P. Declaration of interests: O.N.W., J.M., and P.A.N. are inventors of a patent application in progress that will be filed prior to manuscript publication. J.R.H. is a board member of PACT Pharma and Isoplexis. O.N.W. currently has consulting, equity, and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, Breakthrough Properties, Vida Ventures, Nammi Therapeutics, Two River, Iconovir, Appia BioSciences, Neogene Therapeutics, and Allogene Therapeutics. None of these companies contributed to or directed any of the research reported in this article.
Funding AgencyGrant Number
NIHU01 CA233074
NIHU24 CA248265
Parker Institute for Cancer ImmunotherapyUNSPECIFIED
Broad Stem Cell Research CenterUNSPECIFIED
NIH Predoctoral FellowshipT32 CA009056
Jeff and Liesl Wilke FoundationUNSPECIFIED
Washington State Andy Hill CARE FundUNSPECIFIED
Biomedical Advanced Research and Development AuthorityHHSO10201600031C
W. M. Keck FoundationUNSPECIFIED
Subject Keywords:T cells; SARS-CoV-2; antigen; specific; CD8; TCR; single-cell; COVID-19; immune response; cell therapy
Issue or Number:13
PubMed Central ID:PMC8660260
Record Number:CaltechAUTHORS:20211210-240628000
Persistent URL:
Official Citation: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, HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses, Cell Reports, Volume 37, Issue 13, 2021, 110167, ISSN 2211-1247,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112358
Deposited By: George Porter
Deposited On:10 Dec 2021 19:49
Last Modified:01 Feb 2022 22:54

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