T cell cross-reactivity against SARS-CoV-2 has previously been shown in unexposed individuals. These T cells are thought to arise through exposure to other related coronaviruses such as those causing the common cold. In this preprint, Mahajan et al. used the algorithm ‘OncoPeptVAC’ to predict SARS-CoV-2 immunodominant peptides, some of which induced in vitro responses by T cells isolated from both healthy, unexposed individuals and convalescent patients. The predicted epitopes induced higher levels of CD8+ T cell activation than did overlapping peptide pools of spike protein. T cell receptor (TCR) repertoire profiling of peptide-expanded cultures showed clonal expansion of multiple public TCR sequences recognizing peptides from HCMV, HHV-5 and influenza A virus. This suggests that exposure to these other viruses induces SARS-CoV-2-reactive T cells, which may confer protection against COVID-19.