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Long-persisting SARS-CoV-2-specific CD4+ T cells associated with mild disease and increased cytotoxicity 4 years post COVID-19

A new study, led by researchers at the CAMS Oxford Institute in the Nuffield Department of Medicine and TIDU in the MRC Weatherall Institute of Molecular Medicine, was published in Nature Communications, finding that dominant T cell responses found in many individuals 4yrs after infection are associated with mild COVID-19 disease, and likely play important protective roles to subsequent viral infection events.

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.   

T cells are key players in the immune response to viral infection forming a memory to the virus so that recurrent infections can be more rapidly cleared. As such, we compare the long-term memory T-cell responses following infection with the viral itself, followed by subsequent infections and vaccinations.   

Our analysis focussed on the specific responses against three SARS-CoV-2 protein targets, responses that we have previously shown to be found in a large proportion of the population. Analysis of the receptors on the surface of the T cells identified specific receptors shared amongst many different individuals, which we found to be associated with mild COVID-19, compared to those without this receptor who had more severe disease. Furthermore, these specific receptors were found in individuals analysed before the COVID-19 pandemic, suggesting their existence before the pandemic may have allowed these cells to respond quicker to the virus once encountered.   

Further investigation of the function of these cells revealed that 3-4yrs after infection, the cells exhibited greater cytotoxic potential compared to cells 1-3months after infection, which was associated with the ability of these cells to suppress the replication of the virus.   

In summary, we identify common public T cell receptors used by dominant SARS-CoV-2 T-cells, associated with mild disease outcome, and likely play important protective roles to subsequent viral infection events.   

Professor Tao Dong, Co-Director of the CAMS Oxford Institute and corresponding author on the study, said: “In this study, we have demonstrated that SARS-CoV-2 spike-specific CD4+ T-cells with public TCR usage, reflecting high precursor frequencies, were associated with milder COVID-19 disease and with increased cytotoxicity four years post COVID-19, suggesting their important protective roles in subsequent viral infection events.”

Read the full paper on the Nature Communications website: 
https://www.nature.com/articles/s41467-025-63711-9