Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals
Scientific Reports volume 11, Article number: 13164 (2021 ) Cite this article
The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. However, our findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.
Uncovering the immunological responses to COVID-19 infection will help in designing and developing next-generation therapies and manage the treatment of critical COVID-19 patients. Many host factors associated with mild or severe disease symptoms have been reported. For example, leukopenia, exhausted CD8 T-cells, higher levels of TH2 cytokines in serum, a high titer of neutralizing antibodies, blunted interferon response, dysregulation of the myeloid cell compartment, activated NK cells, and the size of the naïve T-cell compartment is associated with critically ill patients1,2,3,4,5. This wide range of variable factors shares a common immunological underpinning—that of a systemic dysregulation in immune homeostasis due to the failure of the host immune system to clear the virus during the early stages of the infection6. Animal and human studies have demonstrated that susceptibility to respiratory virus infections is associated with compromised CD8 T-cell immunity7,8,9,10,11. A delay in the activation of CD8 T-cells and a lack of early IFN-γ production by the innate immune arm leads to an increase in viral load triggering overactivation of the innate and the adaptive arm of the immune system leading to a loss of immune homeostasis resulting in severe disease phenotype, including death. Therefore, an early wave of strong CD8 T-cell response may delay viral titer build-up, allowing rapid clearance of the virus by the immune system without perturbing immune homeostasis.
