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SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic 1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4+ T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4+ T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4+ T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.
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“This cross-reactivity largely originates from previous exposure to circulating common cold coronaviruses [110-116].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [114]
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In the citing paper
“SARS-CoV-2 infection elicits a Th1 CD4+ T cell response, with IFNγ and IL-2 being the primary cytokines produced by these cells and some TNFα production as well112,126-129.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [128]
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In the citing paper
“lymphocytes from 20% to 50% of unexposed donors display significant reactivity to SARS-CoV-2 Ag peptide pools (Figure 6).”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [114]
In the citing paper
“the T cell responses against SARS-CoV-2 are highly multi-antigenic and multi-specific, with tens of different epitopes recognized by CD4+ and CD8+ T cells in a given individual.”
From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [52]
In the citing paper
“The dominant cytokine produced by SARS-CoV-2-specific CD4+ T cells from COVID-19 patients is IFNγ (Braun et al., 2020; Grifoni et al., 2020; Rydyznski Moderbacher et al., 2020; Weiskopf et al., 2020), with a clear IFNγ, tumor necrosis factor (TNF), IL-2 protein signature of canonical Th1 cells (Braun et al., 2020; Rydyznski Moderbacher et al., 2020; Peng et al., 2020; Sekine et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Braun et al., 2020
In the citing paper
“In contrast, the strikingly extended absence of SARS-CoV-2-specific CD4+ T cells was associated with severe or fatal COVID-19 (>day 22 PSO in some cases) (Braun et al., 2020; Rydyznski Moderbacher et al., 2020; Tan et al., 2020a).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Braun et al., 2020
In the citing paper
“In contrast, substantial cross-reactive T cell memory has been reported, measurable in ∼28%–50% of people, depending on the study (Le Bert et al., 2020; Braun et al., 2020; Grifoni et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Braun et al., 2020
In the citing paper
“Specifically, when compared to those with mild COVID-19, patients with severe disease generated a weaker T cell response to the N-terminal portion of the SARS-CoV-2 S protein, a region that includes the critical receptor-binding domain (RBD)128.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [128]
In the citing paper
“Therefore, many individuals have existing memory T cells that were generated from endemic human coronavirus infections and can cross-react with SARS-CoV-2 epitopes, known as SARS-CoV-2 cross-reactive memory T cells128.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [128]
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Metadata
- Authors
- Braun, J., Loyal, L., Frentsch, M., Wendisch, D., Georg, P., Kurth, F., Hippenstiel, S., Dingeldey, M., Kruse, B., Fauchere, F., Baysal, E., Mangold, M., Henze, L., Lauster, R., Mall, M. A., Beyer, K., Röhmel, J., Voigt, S., Schmitz, J., Miltenyi, S., Demuth, I., Müller, M. A., Hocke, A., Witzenrath, M., Suttorp, N., Kern, F., Reimer, U., Wenschuh, H., Drosten, C., Corman, V. M., Giesecke-Thiel, C., Sander, L. E., & Thiel, A.
- Affiliations
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Charité – Universitätsmedizin Berlin (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Technische Universität Berlin (DE)
- Robert Koch Institute (DE)
- Miltenyi Biotec (Germany) (DE)
- Brighton and Sussex Medical School (GB)
- JPT Peptide Technologies (Germany) (DE)
- Corresponding author
- Sander, Leif Erik
- Thiel, Andreas
- ORCID
- Braun, Julian
- Loyal, Lucie
- Frentsch, Marco
- Wendisch, Daniel
- Georg, Philipp
- Kurth, Florian
- Hippenstiel, Stefan
- Dingeldey, Manuela
- Fauchere, Florent
- Baysal, Emre
- Mangold, Maike
- Henze, Larissa
- Mall, Marcus A.
- Beyer, Kirsten
- Voigt, Sebastian
- Demuth, Ilja
- Müller, Marcel A.
- Hocke, Andreas
- Witzenrath, Martin
- Suttorp, Norbert
- Kern, Florian
- Reimer, Ulf
- Drosten, Christian
- Corman, Victor M.
- Giesecke-Thiel, Claudia
- Sander, Leif Erik
- Thiel, Andreas
- Venue
- Nature
- Published
- 2020-07-29
- Volume
- 587
- Issue
- 7833
- Pages
- 270-274
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3045971896
- Cited by
- 1,310
- References
- 41
- Citations by year
- 2026: 16 · 2025: 37 · 2024: 91 · 2023: 143 · 2022: 283 · 2021: 480 · 2020: 259
- FWCI
- 38.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Sussex Research Online (University of Sussex) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (KFO 339, SFB‐TR84)
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, CD4+ T cells, spike protein, cross-reactive T cells, HCoV-229E, HCoV-OC43, C-terminal epitope, T cell immunity, COVID-19 vaccine design, healthy donors
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Adult, Aged, Aged, 80 and over, Cell Line, Cross Reactions, Female, Humans, Lymphocyte Activation, Male, Middle Aged, Pneumonia, Viral, CD4-Positive T-Lymphocytes, Coronavirus Infections, Epitopes, T-Lymphocyte, Coronavirus 229E, Human, Coronavirus OC43, Human, Pandemics, Coronavirus NL63, Human, Healthy Volunteers, Spike Glycoprotein, Coronavirus
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