CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses

Lineburg, Katie E.; Grant, Emma J.; Swaminathan, Srividhya; Chatzileontiadou, Demetra S.M.; Szeto, Christopher; Sloane, Hannah; Panikkar, Archana; Raju, Jyothy; Crooks, Pauline; Rehan, Sweera; Nguyen, Andrea T.; Lekieffre, Lea; Neller, Michelle A.; Marcus Tong, Zhen Wei; Jayasinghe, Dhilshan; Chew, Keng Yih; Lobos, Christian A.; Halim, Hanim; Burrows, Jacqueline M.; Riboldi-Tunnicliffe, Alan; Chen, Weisan; D’Orsogna, Lloyd; Khanna, Rajiv; Short, Kirsty R.; Smith, Corey; Gras, Stephanie

Efforts are being made worldwide to understand the immune response to SARS-CoV-2, the virus responsible for the COVID-19 pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response. In vitro peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity towards circulating OC43 and HKU-1 beta coronaviruses, but not 229E or NL63 alpha coronaviruses, due to different peptide conformations. TCR sequencing indicated cross-reactivity was driven by private T cell receptor repertoires with a bias for TRBV27 and a long CDR3β loop. Together, our findings demonstrate the basis of selective T cell cross-reactivity towards an immunodominant SARS-CoV-2 epitope and its homologues from seasonal coronaviruses, suggesting long-lived protective immunity.