In summary, here we identified more than 140 human T cell epitopes derived from across the genome of SARS-CoV-2. We provide direct evidence that numerous CD4+ T cells that react to SARS-CoV-2 epitopes actually cross-react with corresponding homologous sequences from any of multiple different commonly circulating HCoVs, and that these reactive cells are largely canonical memory CD4+ T cells. These finding of cross-reactive HCoV T cell specificities are stark contrast to HCoV neutralizing antibodies, which are HCoV species-specific and did not show cross-reactivity against SARS-CoV-2 RBD (33–35). Based on these data, it is plausible to hypothesize that pre-existing cross-reactive HCoV CD4+ T cell memory in some donors could be a contributing factor to variations in COVID-19 patient disease outcomes, but this is at present highly speculative (36).
Abstract
Many unknowns exist about human immune responses to the SARS-CoV-2 virus. SARS-CoV-2 reactive CD4+ T cells have been reported in unexposed individuals, suggesting pre-existing cross-reactive T cell memory in 20-50% of people. However, the source of those T cells has been speculative. Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2-specific CD4+ T cell repertoire. We demonstrate a range of pre-existing memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses HCoV-OC43, HCoV-229E, HCoV-NL63, or HCoV-HKU1. Thus, variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the extensive heterogeneity observed in COVID-19 disease.
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