Throughout the COVID-19 pandemic, research has centred on understanding why some people infected with the SARS-CoV-2 virus experience severe disease. However, 10-30% of individuals do not show any symptoms despite been infected with the virus. Investigating asymptomatic infection could shed light on features of the immune system that help to eliminate SARS-CoV-2 that could be leverage for future therapeutics.
We recently showed that there is a strong association between Human Leukocyte Antigen (HLA)-B*15:01 and asymptomatic COVID-19, and that this genetic association is due to pre-existing T cell immunity. We identified shared T cell receptors (TCR) across multiple individuals, which is surprising given the enormous diversity of TCRs (> 1018). Those shared TCRs were exhibiting high affinity for the spike-derived peptide (NQK), cross-reactivity against seasonal coronaviruses derived peptide and polyfunctionality that is a landmark feature of cytotoxic killer T cells.
Here, we reveal details of the molecular basis using X-ray crystallography, including the crystal structure of a shared TCR in complex with the NQK-HLA-B*15:01 showing a new non-typical binding, underpinning T cell cross-reactivity. Furthermore, we reveal significant differences in the T cell responses between HLA-B*15:01+ asymptomatic/mild infection compared to moderate/severe infection using immunological assays. We hope that such knowledge could inform the design and development of future therapeutics for COVID-19. More broadly, identifying genetic factors that control the course of the disease could begin to explain the wide variation in how people respond to SARS-CoV-2, and other viral infections.