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SARS-CoV-2, the virus causing COVID-19, has dramatically altered life around the globe. For antiviral therapeutics like vaccines to work, scientists need to know which areas of the virus - or epitopes - can activate immune cells called T cells. The authors of this study used computer algorithms to predict which epitopes of SARS-CoV-2 could activate T cells. To confirm those predictions, they measured how T cells responded using blood samples from two groups of people: 180 individuals previously infected with SARS-CoV-2 and 185 individuals not exposed to the virus. The team discovered that some epitopes were specific to SARS-CoV-2, while others were cross-reactivethey were similar enough to epitopes on common-cold-causing viruses to prompt a T-cell response. In fact, 81% of unexposed individuals had some T-cell response to these epitopes. While this suggests at least some built-in immune protection from SARS-CoV-2, T-cell responses in previously infected people were much more robust than those in unexposed individuals. Individuals with a broader T-cell response to viral epitopes reported less-severe COVID-19 symptoms, suggesting that people with some T-cell recognition of SARS-CoV-2 prior to infection may exhibit less severe illness. Additional studies comparing the same subjects before and after infection are needed to understand how T-cell cross-reactivity relates to immunity and symptom severity. Nevertheless, this study suggests that promoting T-cell responses to SARS-CoV-2 may be important for designing effective therapeutic and preventive measures.

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The SARS-CoV-2 pandemic calls for the rapid development of diagnostic, preventive, and therapeutic approaches. CD4+ and CD8+ T cell-mediated immunity is central for control of and protection from viral infections[1-3]. A prerequisite to characterize T-cell immunity, but also for the development of vaccines and immunotherapies, is the identification of the exact viral T-cell epitopes presented on human leukocyte antigens (HLA)[2-8]. This is the first work identifying and characterizing SARS-CoV-2-specific and cross-reactive HLA class I and HLA-DR T-cell epitopes in SARS-CoV-2 convalescents (n = 180) as well as unexposed individuals (n = 185) and confirming their relevance for immunity and COVID-19 disease course. SARS-CoV-2-specific T-cell epitopes enabled detection of post-infectious T-cell immunity, even in seronegative convalescents. Cross-reactive SARS-CoV-2 T-cell epitopes revealed preexisting T-cell responses in 81% of unexposed individuals, and validation of similarity to common cold human coronaviruses provided a functional basis for postulated heterologous immunity[9] in SARS-CoV-2 infection[10,11]. Intensity of T-cell responses and recognition rate of T-cell epitopes was significantly higher in the convalescent donors compared to unexposed individuals, suggesting that not only expansion, but also diversity spread of SARS-CoV-2 T-cell responses occur upon active infection. Whereas anti-SARS-CoV-2 antibody levels were associated with severity of symptoms in our SARS-CoV-2 donors, intensity of T-cell responses did not negatively affect COVID-19 severity. Rather, diversity of SARS-CoV-2 T-cell responses was increased in case of mild symptoms of COVID-19, providing evidence that development of immunity requires recognition of multiple SARS-CoV-2 epitopes. Together, the specific and cross-reactive SARS-CoV-2 T-cell epitopes identified in this work enable the identification of heterologous and post-infectious T-cell immunity and facilitate the development of diagnostic, preventive, and therapeutic measures for COVID-19.

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