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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, has found that dominant T cell responses years after infection are associated with mild COVID-19 disease, and likely play important protective roles to following viral infections.

The recent COVID-19 pandemic left behind the lingering question of whether new variants of concern might cause further waves of infection. This is why it’s important to investigate the long-term protection gained through 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 cleared faster. Because of this, researchers have compared the long-term memory T-cell responses following infection with the viral itself, followed by subsequent infections and vaccinations.   

In their new study, the researchers’ analysis focussed on the specific responses against three SARS-CoV-2 protein targets, responses that were previously found in a large proportion of the population. Analysis of the receptors on the surface of the T cells identified specific receptors shared in many different individuals, which were 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 3-4 years after infection, the cells exhibited greater cytotoxic potential compared to cells 1-3 months after infection, which was associated with the ability of these cells to suppress the replication of the virus.   

In their findings, the team now identify common public T cell receptors used by dominant SARS-CoV-2 T-cells as 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