SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition
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Abstract
T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.
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This cross-reactivity largely originates from previous exposure to circulating common cold coronaviruses.
“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 [115]
The ‘Cross-reactive T cell responses in unexposed individuals’ section reports pre-existing responses and similarities between recognized SARS-CoV-2 epitopes and seasonal common cold coronaviruses. The Discussion treats this as a basis for cross-reactivity, but the paper does not establish that previous exposure to those viruses accounts for most of it. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLymphocytes from 20% to 50% of unexposed donors display significant reactivity to SARS-CoV-2 Ag peptide pools.
“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 [115]
The Discussion reports SARS-CoV-2-reactive T cells in unexposed donors and notes earlier studies using peptide pools. But this paper reports responses in 81% of unexposed donors after 12-day pre-stimulation, not 20%–50%; its ex vivo analysis detected none of 42 unexposed donors. The claimed percentage is therefore not supported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredT 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.
“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 [62]
Spike, M, and nucleocapsid are the most prominent targets of SARS-CoV-2-specific CD4+ T cells, with substantial responses also against ORF3a and nsp3.
“Spike, M, and nucleocapsid are the most prominent targets of SARS-CoV-2-specific CD4+ T cells (Grifoni et al., 2020), with substantial responses also against ORF3a and nsp3 (Le Bert et al., 2020; Grifoni et al., 2020; Nelde et al., 2021; Oja et al., 2020; Peng et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Nelde et al., 2021
Multiple reports describe healthy individuals controlling SARS-CoV-2 infection with little to no detectable neutralizing or RBD IgG antibodies while having significant SARS-CoV-2-specific T cell memory.
“Separately, there are multiple reports of healthy individuals successfully controlling a SARS-CoV-2 infection with little to no neutralizing (or RBD IgG) antibodies detectable post-infection, while having significant SARS-CoV-2-specific T cell memory (Rydyznski Moderbacher et al., 2020; Nelde et al., 2021; Schulien et al., 2020; Sekine et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Nelde et al., 2021
At least some individuals are low or negative to commercial IgG assays while retaining detectable SARS-CoV-2 CD4+ T cells, representing 1%-10% of PCR-confirmed SARS-CoV-2 infections.
“at least some individuals are low or negative to commercial IgG assays, while retaining detectable SARS-CoV-2 CD4+ T cells. Current estimates are these individuals represent 1%–10% of PCR-confirmed SARS-CoV-2 infections (Gudbjartsson et al., 2020; Lipsitch et al., 2020; Nelde et al., 2021; Schwarzkopf et al., 2021; Sekine et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Nelde et al., 2021
Current evidence suggests that an early, robust and diverse T cell response against SARS-CoV-2 correlates with milder COVID-19 outcomes.
“Current evidence suggests an early, robust, and diverse T cell response directed against SARS-CoV-2 correlates with milder COVID-19 outcomes126,131,132”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [131]
Severe COVID-19 is associated with reduced TCR diversity against SARS-CoV-2 epitopes.
“Severe COVID-19 has been associated with lower TCR diversity against SARS-CoV-2 epitopes131,132.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [131]
Severe COVID-19 may be associated with a lack of pre-existing SARS-CoV-2 cross-reactive memory T cells in the TCR repertoire.
“Another study concluded that severe COVID-19 may even be associated with a lack of these pre-existing SARS-CoV-2 cross-reactive memory T cells in the TCR repertoire131.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [131]
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- Authors
- Nelde, A., Bilich, T., Heitmann, J. S., Maringer, Y., Salih, H. R., Roerden, M., Lübke, M., Bauer, J., Rieth, J., Wacker, M., Peter, A., Hörber, S., Traenkle, B., Kaiser, P. D., Rothbauer, U., Becker, M., Junker, D., Krause, G., Strengert, M., Schneiderhan-Marra, N., Templin, M. F., Joos, T. O., Kowalewski, D. J., Stos-Zweifel, V., Fehr, M., Rabsteyn, A., Mirakaj, V., Karbach, J., Jäger, E., Graf, M., Gruber, L.-C., Rachfalski, D., Preuß, B., Hagelstein, I., Märklin, M., Bakchoul, T., Gouttefangeas, C., Kohlbacher, O., Klein, R., Stevanović, S., Rammensee, H.-G., & Walz, J. S.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- German Cancer Research Center (DE)
- University of Tübingen (DE)
- Natural and Medical Sciences Institute (DE)
- Medizinische Hochschule Hannover (DE)
- Immatics Biotechnologies (Germany) (DE)
- University Children's Hospital Tübingen (DE)
- Krankenhaus Nordwest (DE)
- Corresponding author
- Walz, Juliane S.
- ORCID
- Nelde, Annika
- Bilich, Tatjana
- Heitmann, Jonas S.
- Maringer, Yacine
- Salih, Helmut R.
- Roerden, Malte
- Lübke, Maren
- Bauer, Jens
- Wacker, Marcel
- Peter, Andreas
- Hörber, Sebastian
- Traenkle, Bjoern
- Kaiser, Philipp D.
- Rothbauer, Ulrich
- Becker, Matthias
- Junker, Daniel
- Krause, Gérard
- Strengert, Monika
- Schneiderhan-Marra, Nicole
- Templin, Markus F.
- Joos, Thomas O.
- Kowalewski, Daniel J.
- Rabsteyn, Armin
- Mirakaj, Valbona
- Karbach, Julia
- Jäger, Elke
- Preuß, Beate
- Märklin, Melanie
- Bakchoul, Tamam
- Gouttefangeas, Cécile
- Kohlbacher, Oliver
- Klein, Reinhild
- Stevanović, Stefan
- Rammensee, Hans-Georg
- Walz, Juliane S.
- Venue
- Nature Immunology
- Published
- 2020-09-30
- Volume
- 22
- Issue
- 1
- Pages
- 74-85
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W3089759643
- Cited by
- 582
- References
- 54
- Citations by year
- 2026: 21 · 2025: 46 · 2024: 60 · 2023: 111 · 2022: 135 · 2021: 177 · 2020: 30 · 2014: 1 · 2012: 1
- FWCI
- 36.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Immunology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wilhelm Sander-Stiftung (2016.177.2)
- European Commission (HORIZON2020, 101003480)
- Deutsche Forschungsgemeinschaft (DJCLS 05R/2017, 2451-0-0, EXC2180, EXC 2180—390 900 677, WA4608/1-2, 2016.177.2, 2581-0-0, 390900677, FKZ:01KI20130)
- Eberhard Karls Universität Tübingen (390900677, 2581-0-0, 2451-0-0)
- Bundesministerium für Bildung und Forschung (EXC2180–390900677, FKZ:01KI20130, 2016.177.2, 01KI20130, WA 4608/1-2, DJCLS 05R/2017)
- José Carreras Leukämie-Stiftung (WA 4608/1-2, 2451-0-0, EXC2180-390900677, DJCLS 05 R/2017, Grant DJCLS 05 R/2017, 2016.177.2, FKZ:01KI20130)
- Deutschen Konsortium für Translationale Krebsforschung (DJCLS 05R/2017, WA 4608/1-2, FKZ:01KI20130, EXC2180-390900677, 2016.177.2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- SARS-CoV-2, COVID-19 pandemic, T cell epitopes, heterologous immunity, T cell cross-reactivity, common cold coronaviruses, epitope diversity, mild COVID-19, T cell immunity, vaccine development
- MeSH terms
- COVID-19, SARS-CoV-2, Cross Reactions, HLA-DR Antigens, Humans, Immunologic Memory, Peptides, T-Lymphocytes, Viral Vaccines, Histocompatibility Antigens Class I, Epitopes, T-Lymphocyte
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