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SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19
Open accessPublished version of a preprint
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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“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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“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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Clustal W and Clustal X version 2.0
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La certeza de lo impredecible: Cultura Educación y Sociedad en tiempos de COVID19
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An interactive web-based dashboard to track COVID-19 in real time
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Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Walls, A. C., Park, Y.-J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020) · doi:10.1101/2020.02.19.956581 · Cited by 8,586
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Self-citationVirological assessment of hospitalized patients with COVID-2019
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Adaptive immunity to SARS-CoV-2 and COVID-19
Sette, A., & Crotty, S. (2021) · Cell · doi:10.1016/j.cell.2021.01.007 · Cited by 1,860
Rydyznski Moderbacher, C., Ramirez, S. I., Dan, J. M., Grifoni, A., Hastie, K. M., Weiskopf, D., Belanger, S., Abbott, R. K., Kim, C., Choi, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.038 · Cited by 1,790
Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19
Sekine, T., Perez-Potti, A., Rivera-Ballesteros, O., Strålin, K., Gorin, J.-B., Olsson, A., Llewellyn-Lacey, S., Kamal, H., Bogdanovic, G., Muschiol, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.017 · Cited by 1,788
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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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