Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

Grifoni, Alba; Weiskopf, Daniela; Ramirez, Sydney I.; Mateus, Jose; Dan, Jennifer M.; Moderbacher, Carolyn Rydyznski; Rawlings, Stephen A.; Sutherland, Aaron; Premkumar, Lakshmanane; Jadi, Ramesh S.; Marrama, Daniel; de Silva, Aravinda M.; Frazier, April; Carlin, Aaron; Greenbaum, Jason A.; Peters, Bjoern; Krammer, Florian; Smith, Davey M.; Crotty, Shane; Sette, Alessandro

Summary Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.