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Title	Low-Avidity CD4(+) T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19.
Author	Bacher, Petra; Rosati, Elisa; Esser, Daniela; Martini, Gabriela Rios; Saggau, Carina; Schiminsky, Esther; Dargvainiene, Justina; Schroder, Ina; Wieters, Imke; Khodamoradi, Yascha; Eberhardt, Fabian; Vehreschild, Maria J G T; Neb, Holger; Sonntagbauer, Michael; Conrad, Claudio; Tran, Florian; Rosenstiel, Philip; Markewitz, Robert; Wandinger, Klaus-Peter; Augustin, Max; Rybniker, Jan; Kochanek, Matthias; Leypoldt, Frank; Cornely, Oliver A; Koehler, Philipp; Franke, Andre; Scheffold, Alexander
Journal	Immunity	Publication Year/Month	2020-Dec
PMID	33296686	PMCID	PMC7689350
Affiliation + expend	1.Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Germany; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. Electronic address: p.bacher@ikmb.uni-kiel.de.
	2.Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
	3.Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/ Lubeck, Germany.
	4.Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Germany; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
	5.Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Germany.
	6.Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt & Goethe University Frankfurt, Frankfurt am Main, Germany.
	7.Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
	8.Department of Internal Medicine, Hospital of Preetz, Preetz, Germany.
	9.Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Department of Internal Medicine I, UKSH Kiel, Germany.
	10.University of Cologne, Medical Faculty and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; University of Cologne, Medical Faculty and University Hospital Cologne, German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
	11.University of Cologne, Medical Faculty and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany.
	12.Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/ Lubeck, Germany; Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.
	13.University of Cologne, Medical Faculty and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; University of Cologne, Medical Faculty and University Hospital Cologne, German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany; Clinical Trials Centre Cologne, ZKS Koln, Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
	14.University of Cologne, Medical Faculty and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.

Abstract

CD4(+) T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4(+) T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4(+) memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4(+) T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4(+) T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

Keywords

ARTE

COVID-19

SARS-CoV-2

T cell cross-reactivity

antigen-reactive T cell enrichment

antigen-specific T cells

common cold coronavirus

human coronavirus

pre-existing memory

MeSH terms

CD4-Positive T-Lymphocytes/*immunology