Long-persisting SARS-CoV-2 spike-specific CD4+ T cells associated with mild disease and increased cytotoxicity post COVID-19

The recent COVID-19 pandemic left behind the lingering question as whether new variants of concern might cause further waves of infection. Thus, it is important to investigate the long-term protection gained via vaccination or exposure to the SARS-CoV-2 virus. Here we compare the evolution of memory T-cell responses following primary infection with subsequent antigen exposures. Single-cell TCR analysis of three dominant SARS-CoV-2 spike-specific CD4<sup>+</sup> T-cell responses identifies the dominant public TCRα clonotypes pairing with diverse TCRβ clonotypes that associated with mild disease at primary infection. These clonotypes are found at higher frequencies in pre-pandemic repertoires compared to other epitope-specific clonotypes. Longitudinal transcriptomics and TCR analysis, combined with functional evaluation, reveals that the clonotypes persisting 3-4 years post initial infection exhibit distinct functionality compared to those that were lost. Furthermore, spike-specific CD4<sup>+</sup> T cells at this time point show decreased Th1 signatures and enhanced GZMA-driven cytotoxic transcriptomic profiles that were independent of TCR clonotype and associated with viral suppression. In summary, we identify common public TCRs used by immunodominant spike-specific memory CD4<sup>+</sup> T-cells, associated with mild disease outcome, which likely play important protective roles to subsequent viral infection events.

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Publication Details

Journal
Nature Communications
Published
2025-10-01
DOI
https://doi.org/10.1038/s41467-025-63711-9
Citations
2
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
2.79

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article

Long-persisting SARS-CoV-2 spike-specific CD4+ T cells associated with mild disease and increased cytotoxicity post COVID-19

Wanwisa Dejnirattisa, Peter A. C. Wing, Román Fischer, Benedikt Mathias Kessler et al.
2 citations
Nature Communications
SARS-CoV-2 and COVID-19 Research
2.79
article

Long-persisting SARS-CoV-2 spike-specific CD4+ T cells associated with mild disease and increased cytotoxicity post COVID-19

Wanwisa Dejnirattisa, Peter A. C. Wing, Román Fischer, Benedikt Mathias Kessler, Iolanda Vendrell, Elie Antoun, Craig Waugh, Jane A. McKeating, Alexander J. Mentzer, Timothy Rostron, Graham S. Ogg, Julian Charles Knight, Yanchun Peng, Anastasia Fries, Jeremy Fry, Tao Dong, Zixi Yin, Gavin Robert Screaton, Wenbo Wang, Chang Liu, Xuan Yao, Kevin Clark, Juthathip Mongkolsapaya, Paul Sopp, Guihai Liu, Danning Dong, Piyada Supasa
article en
2 citations

Abstract

The recent COVID-19 pandemic left behind the lingering question as whether new variants of concern might cause further waves of infection. Thus, it is important to investigate the long-term protection gained via vaccination or exposure to the SARS-CoV-2 virus. Here we compare the evolution of memory T-cell responses following primary infection with subsequent antigen exposures. Single-cell TCR analysis of three dominant SARS-CoV-2 spike-specific CD4<sup>+</sup> T-cell responses identifies the dominant public TCRα clonotypes pairing with diverse TCRβ clonotypes that associated with mild disease at primary infection. These clonotypes are found at higher frequencies in pre-pandemic repertoires compared to other epitope-specific clonotypes. Longitudinal transcriptomics and TCR analysis, combined with functional evaluation, reveals that the clonotypes persisting 3-4 years post initial infection exhibit distinct functionality compared to those that were lost. Furthermore, spike-specific CD4<sup>+</sup> T cells at this time point show decreased Th1 signatures and enhanced GZMA-driven cytotoxic transcriptomic profiles that were independent of TCR clonotype and associated with viral suppression. In summary, we identify common public TCRs used by immunodominant spike-specific memory CD4<sup>+</sup> T-cells, associated with mild disease outcome, which likely play important protective roles to subsequent viral infection events.

Nature CommunicationsVol. 16(1)
Siriraj Hospital (TH), Centre for Human Genetics (GB), Mahidol University (TH), Angkor Hospital for Children (KH), Discovery Centre (CA), Nuffield Orthopaedic Centre (GB), University of Oxford (GB), MRC Weatherall Institute of Molecular Medicine (GB), MRC Human Immunology Unit (GB), Oxford BioMedica (United Kingdom) (GB), Science Oxford (GB), ProImmune (United Kingdom) (GB)
Wellcome Trust, National Institute for Health and Care Research, China Scholarship Council, Chinese Academy of Medical Sciences, National Institutes of Health, Medical Research Council, NIHR Oxford Biomedical Research Centre
Openalex Percentile: Top 9%
SARS-CoV-2 and COVID-19 Research
2.79
DOIOpen Access PDFOpenAlex
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