CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naïve precursor frequency and T cell receptor promiscuity

Nguyen, Thi H.O.; Rowntree, Louise C.; Petersen, Jan; Chua, Brendon Y.; Hensen, Luca; Kedzierski, Lukasz; van de Sandt, Carolien E.; Chaurasia, Priyanka; Tan, Hyon-Xhi; Habel, Jennifer R.; Zhang, Wuji; Allen, Lily; Earnest, Linda; Mak, Kai Yan; Juno, Jennifer A.; Wragg, Kathleen; Mordant, Francesca L.; Amanat, Fatima; Krammer, Florian; Mifsud, Nicole A.; Doolan, Denise L.; Flanagan, Katie L.; Sonda, Sabrina; Kaur, Jasveen; Wakim, Linda M.; Westall, Glen P.; James, Fiona; Mouhtouris, Effie; Gordon, Claire L.; Holmes, Natasha E.; Smibert, Olivia C.; Trubiano, Jason A.; Cheng, Allen C.; Harcourt, Peter; Clifton, Patrick; Crawford, Jeremy Chase; Thomas, Paul G.; Wheatley, Adam K.; Kent, Stephen J.; Rossjohn, Jamie; Torresi, Joseph; Kedzierska, Katherine

To better understand primary and recall T cell responses during COVID-19, it is important to examine unmanipulated SARS-CoV-2-specific T cells. Using peptide-HLA tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed towards subdominant epitopes – B7/N257, A2/S269 and A24/S1208 – CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequency in pre-pandemic samples, and at increased frequency during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults and elderly individuals predominantly displayed a naïve phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαβ repertoires and promiscuous αβ-TCR pairing within B7/N105 +CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαβ diversity within immunodominant B7/N105-specific CD8+ T cells, and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.