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

Guihai Liu, Elie Antoun, Anastasia Fries, Xuan Yao, Zixi Yin, Danning Dong, Wenbo Wang, Peter A. C. Wing, Wanwisa Dejnirattisa, Piyada Supasa, Chang Liu, Timothy Rostron, Craig Waugh, Kevin Clark, Paul Sopp, Jeremy W. Fry, Iolanda Vendrell, Jane A. McKeating, Juthathip Mongkolsapaya, Gavin R. Screaton, Benedikt M. Kessler, Roman Fisher, Graham Ogg, Alexander J. Mentzer, Julian C. Knight, Yanchun Peng and Tao Dong ()
Additional contact information
Guihai Liu: University of Oxford
Elie Antoun: University of Oxford
Anastasia Fries: University of Oxford
Xuan Yao: University of Oxford
Zixi Yin: University of Oxford
Danning Dong: University of Oxford
Wenbo Wang: University of Oxford
Peter A. C. Wing: University of Oxford
Wanwisa Dejnirattisa: University of Oxford
Piyada Supasa: University of Oxford
Chang Liu: University of Oxford
Timothy Rostron: University of Oxford
Craig Waugh: University of Oxford
Kevin Clark: University of Oxford
Paul Sopp: University of Oxford
Jeremy W. Fry: ProImmune Limited
Iolanda Vendrell: University of Oxford
Jane A. McKeating: University of Oxford
Juthathip Mongkolsapaya: University of Oxford
Gavin R. Screaton: University of Oxford
Benedikt M. Kessler: University of Oxford
Roman Fisher: University of Oxford
Graham Ogg: University of Oxford
Alexander J. Mentzer: University of Oxford
Julian C. Knight: University of Oxford
Yanchun Peng: University of Oxford
Tao Dong: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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+ 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+ 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+ T-cells, associated with mild disease outcome, which likely play important protective roles to subsequent viral infection events.

Date: 2025
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DOI: 10.1038/s41467-025-63711-9

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