SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

The baseline composition of T cells directly impacts later response to pathogens, but the complexity of precursor states remains poorly defined. Here, we examined the baseline state of SARS-CoV-2-specific T cells in unexposed individuals. SARS-CoV-2-specific CD4(+) T cells were identified in pre-pandemic blood samples by class II peptide-MHC tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2-specific T cells that expressed memory phenotype markers. Integrated phenotypic analyses demonstrated diverse pre-existing memory states that included cells with distinct polarization states and trafficking potential to barrier tissues. T cell clones generated from tetramer-labeled cells cross-reacted with antigens from commensal bacteria in the skin and gastrointestinal tract. Direct ex vivo tetramer staining for one spike-specific population showed a similar level of cross-reactivity to sequences from endemic coronavirus and commensal bacteria. These data highlight the complexity of precursor T cell repertoire and implicate non-infectious exposures to common microbes as a key factor that shapes human pre-existing immunity to SARS-CoV-2.