- Mateus, Jose;
- Grifoni, Alba;
- Tarke, Alison;
- Sidney, John;
- Ramirez, Sydney I;
- Dan, Jennifer M;
- Burger, Zoe C;
- Rawlings, Stephen A;
- Smith, Davey M;
- Phillips, Elizabeth;
- Mallal, Simon;
- Lammers, Marshall;
- Rubiro, Paul;
- Quiambao, Lorenzo;
- Sutherland, Aaron;
- Yu, Esther Dawen;
- da Silva Antunes, Ricardo;
- Greenbaum, Jason;
- Frazier, April;
- Markmann, Alena J;
- Premkumar, Lakshmanane;
- de Silva, Aravinda;
- Peters, Bjoern;
- Crotty, Shane;
- Sette, Alessandro;
- Weiskopf, Daniela
Many unknowns exist about human immune responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. SARS-CoV-2-reactive CD4+ T cells have been reported in unexposed individuals, suggesting preexisting cross-reactive T cell memory in 20 to 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 preexisting memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses human coronavirus (HCoV)-OC43, HCoV-229E, HCoV-NL63, and 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 coronavirus disease 2019 (COVID-19) disease.