Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’

David S. Fischer, Meshal Ansari, Karolin I. Wagner, Sebastian Jarosch, Yiqi Huang, Christoph H. Mayr, Maximilian Strunz, Niklas J. Lang, Elvira D’Ippolito, Monika Hammel, Laura Mateyka, Simone Weber, Lisa S. Wolff, Klaus Witter, Isis E. Fernandez, Gabriela Leuschner, Katrin Milger, Marion Frankenberger, Lorenz Nowak, Katharina Heinig-Menhard, Ina Koch, Mircea G. Stoleriu, Anne Hilgendorff, Jürgen Behr, Andreas Pichlmair, Benjamin Schubert, Fabian J. Theis, Dirk H. Busch, Herbert B. Schiller () and Kilian Schober ()
Additional contact information
David S. Fischer: Helmholtz Zentrum München, Neuherberg
Meshal Ansari: Helmholtz Zentrum München, Neuherberg
Karolin I. Wagner: Immunology and Hygiene, Technische Universität München (TUM)
Sebastian Jarosch: Immunology and Hygiene, Technische Universität München (TUM)
Yiqi Huang: Technische Universität München (TUM)
Christoph H. Mayr: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Maximilian Strunz: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Niklas J. Lang: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Elvira D’Ippolito: Immunology and Hygiene, Technische Universität München (TUM)
Monika Hammel: Immunology and Hygiene, Technische Universität München (TUM)
Laura Mateyka: Immunology and Hygiene, Technische Universität München (TUM)
Simone Weber: Immunology and Hygiene, Technische Universität München (TUM)
Lisa S. Wolff: Technische Universität München (TUM)
Klaus Witter: Cell Therapeutic Agents and Hemostaseology, LMU Munich
Isis E. Fernandez: University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for lung research (DZL)
Gabriela Leuschner: University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for lung research (DZL)
Katrin Milger: University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for lung research (DZL)
Marion Frankenberger: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Lorenz Nowak: Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Munich and Gauting
Katharina Heinig-Menhard: Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Munich and Gauting
Ina Koch: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Mircea G. Stoleriu: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Anne Hilgendorff: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Jürgen Behr: University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for lung research (DZL)
Andreas Pichlmair: Technische Universität München (TUM)
Benjamin Schubert: Helmholtz Zentrum München, Neuherberg
Fabian J. Theis: Helmholtz Zentrum München, Neuherberg
Dirk H. Busch: Immunology and Hygiene, Technische Universität München (TUM)
Herbert B. Schiller: Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
Kilian Schober: Immunology and Hygiene, Technische Universität München (TUM)

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for ‘reverse phenotyping’. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

Date: 2021
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DOI: 10.1038/s41467-021-24730-4

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