Potent SARS-CoV-2-Specific T Cell Immunity and Low Anaphylatoxin Levels Correlate With Mild Disease Progression in COVID-19 Patients
Open accessAbstract
T cells play a fundamental role in the early control and clearance of many viral infections of the respiratory system. In SARS-CoV-2-infected individuals, lymphopenia with drastically reduced CD4+ and CD8+ T cells correlates with Coronavirus disease 2019 (COVID-19)-associated disease severity and mortality. In this study, we characterized cellular and humoral immune responses induced in patients with mild, severe and critical COVID-19. Peripheral blood mononuclear cells of 37 patients with mild, severe and critical COVID-19 and 10 healthy individuals were analyzed by IFNγ ELISpot and multi-color flow cytometry upon stimulation with peptide pools covering complete immunodominant SARS-CoV-2 matrix, nucleocapsid and spike proteins. In addition SARS-CoV-2 antibody levels, neutralization abilities and anaphylatoxin levels were evaluated by various commercially available ELISA platforms. Our data clearly demonstrates a significantly stronger induction of SARS-CoV-2 specific CD8+ T lymphocytes and higher IFNγ production in patients with mild compared to patients with severe or critical COVID-19. In all patients SARS-CoV-2-specific antibodies with similar neutralizing activity were detected, but highest titers of total IgGs were observed in critical patients. Finally, elevated anaphylatoxin C3a and C5a levels were identified in severe and critical COVID-19 patients probably caused by aberrant immune complex formation due to elevated antibody titers in these patients. Crucially, we provide a full picture of cellular and humoral immune responses of COVID-19 patients and prove that robust polyfunctional CD8+ T cell responses concomitant with low anaphylatoxin levels correlate with mild infections. In addition, our data indicates that high SARS-CoV-2 antibody titers are associated with severe disease progression.
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It is likely that CD8+ T cells contribute to viral clearance in tissues.
“Although the correlates of protection in this study were binding and neutralizing antibody titres34,35, it is likely that CD8+ T cells contribute to viral clearance in tissues36,37.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [36]
The Introduction (page unavailable) says CD8+ T cells play a critical role in viral clearance and associates early CD8+ T-cell immunity with clearance. The study measured cells from blood, however, and the cited passages do not establish clearance specifically in tissues. (LLM, conf=0.82)
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Gebre, M. S., Rauch, S., Roth, N., Yu, J., Chandrashekar, A., Mercado, N. B., He, X., Liu, J., McMahan, K., Martinot, A., et al. (2021) · doi:10.1101/2021.08.13.456316 · Cited by 8 · see citing works
Serum Neutralization Against SARS-CoV-2 Variants Is Heterogenic and Depends on Vaccination Regimen
Jäger, M., Dichtl, S., Bellmann‐Weiler, R., Reindl, M., Lass‐Flörl, C., Wilflingseder, D., & Posch, W. (2022) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiac432 · Cited by 8 · see citing works
Self-citationIm, K.-I., Kim, N., Lee, J.-S., Oh, U.-H., Lee, H. W., Lee, D., Min, G. J., Lee, R., Lee, J., Kim, S., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910512 · Cited by 6 · see citing works
Immune Responses Against SARS-CoV-2 WT and Delta Variant in Elderly BNT162b2 Vaccinees
Jäger, M., Sonnleitner, S. T., Dichtl, S., Lafon, E., Diem, G., Walder, G., Lass‐Flörl, C., Wilflingseder, D., & Posch, W. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.868361 · Cited by 6 · see citing works
Self-citationWang, D., Gao, Y., Lai, Q.-Q., Wu, D., Liu, H., Meng, H., Wang, X.-T., Tang, Y.-J., Xu, J., Zhang, J., et al. (2024) · Journal of International Medical Research · doi:10.1177/03000605241236278 · Cited by 5 · see citing works
Chaiwong, W., Takheaw, N., Laopajon, W., Pata, S., Duangjit, P., Inchai, J., Pothirat, C., Bumroongkit, C., Deesomchok, A., Theerakittikul, T., et al. (2022) · Vaccines · doi:10.3390/vaccines10122176 · Cited by 5 · see citing works
Knell, A. I., Boehm, A., Jäger, M., Kerschbaum, J., Engl, S., Rudnicki, M., Buchwinkler, L., Bellmann‐Weiler, R., Posch, W., & Weiß, G. (2023) · Microorganisms · doi:10.3390/microorganisms11071756 · Cited by 4 · see citing works
Self-citationJäger, M., Diem, G., Sahanic, S., Fux, V., Griesmacher, A., Lass‐Flörl, C., Wilflingseder, D., Tancevski, I., & Posch, W. (2023) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiad057 · Cited by 4 · see citing works
Self-citationViurcos-Sanabria, R., Manjarrez‐Reyna, A. N., Solleiro-Villavicencio, H., Rizo-Téllez, S. A., Méndez-García, L. A., Sanabria, V. S. V., González-Sanabria, J., Arroyo-Valerio, A., Carrillo-Ruiz, J. D., González-Chávez, A., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.897995 · Cited by 4 · see citing works
Kenno, S., Pedretti, N., Spaggiari, L., Ardizzoni, A., Comar, M., Posch, W., Wheeler, R. T., Peppoloni, S., & Pericolini, E. (2025) · Journal of Fungi · doi:10.3390/jof11070501 · Cited by 2 · see citing works
Self-citationWang, D., & Zhang, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1690298 · Cited by 1 · see citing works
Halim, H. A. E., Brigo, N., Dichtl, S., Seifert, M., Schweighofer, P., Posch, W., Weiß, G., & Wilflingseder, D. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119474 · Cited by 1 · see citing works
Self-citationda Silva, G. C. S., Paraná, V. C., Rego, F. F. D. A., Portela, M., Queiroz, M. B., Coutinho, R., da Silva, C. G. R., Gois, L. L., & Grassi, M. F. R. (2025) · Journal of Infection and Public Health · doi:10.1016/j.jiph.2025.102803 · Cited by 1 · see citing works
Saito, T., Couzinet, A., Murakami, T., Shimomura, M., Suzuki, T., Katayama, Y., & Nakatsura, T. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.149398 · Cited by 1 · see citing works
Blaess, M. F., Sommerfeld, O., Csük, R., & Deigner, H. (2022) · Exploration of Immunology · doi:10.37349/ei.2022.00063 · Cited by 1 · see citing works
Riesgo-Ferreiro, P., Gudimella, R., Bukur, T., Sorn, P., Rösler, T., Schrörs, B., & Löwer, M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.31.478157 · Cited by 1 · see citing works
Antikörperbestimmung nach SARS-CoV-2-Impfung: Sinnvolles Monitoring oder bedeutungslos?
Lotz, C., Herrmann, J., Hübsch, M. E., Notz, Q., & Meybohm, P. (2022) · AINS - Anästhesiologie · Intensivmedizin · Notfallmedizin · Schmerztherapie · doi:10.1055/a-1783-3932
Innate immune responses in COVID-19
Jacotot, E. D., Talamini, L., Bonam, S. R., Vieira, A. T., Frémeaux‐Bacchi, V., Radic, M. Z., Dragon‐Durey, M., Lozano, J. M., Saia, R. S., & Muller, S. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-18566-3.00041-4
Mayr, W., Knell, A. I., Boehm, A. K., Jäger, M., Ennemoser, L., Griesmacher, A., Bellmann‐Weiler, R., Koch, R., Tilg, H., Posch, W., et al. (2026) · Vaccine · doi:10.1016/j.vaccine.2026.129224
Self-citation
- Authors
- Lafon, E., Diem, G., Witting, C., Zaderer, V., Bellmann-Weiler, R. M., Reindl, M., Bauer, A., Griesmacher, A., Fux, V., Hoermann, G., Miller, C., Zabernigg, A., Wöll, E., Wilflingseder, D., Lass-Flörl, C., & Posch, W.
- Affiliations
- Innsbruck Medical University (AT)
- Corresponding author
- Posch, Wilfried
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2021-06-14
- Volume
- 12
- Pages
- 684014-684014
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC8237940
- OpenAlex
- W3166555921
- Cited by
- 46
- References
- 51
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 14 · 2022: 18 · 2021: 4
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Oesterreichische Nationalbank (P17614, P19633)
- Austrian Science Fund (P34070-B, P33512-B)
- Tiroler Wissenschaftsförderung (70454)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- COVID-19 pandemic, SARS-CoV-2, CD8+ T cell responses, anaphylatoxins, C3a, C5a, disease severity, interferon-gamma, neutralizing antibodies, antibody titers, immune complex formation, lymphopenia, humoral immune response
- MeSH terms
- COVID-19, SARS-CoV-2, Adult, Aged, Aged, 80 and over, Anaphylatoxins, Antibodies, Viral, Female, Flow Cytometry, Humans, Interferon-gamma, Male, Middle Aged, CD8-Positive T-Lymphocytes, Disease Progression, Immunity, Humoral, Enzyme-Linked Immunospot Assay, Patient Acuity
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