PT - JOURNAL ARTICLE AU - Laurent Bartolo AU - Sumbul Afroz AU - Yi-Gen Pan AU - Ruozhang Xu AU - Lea Williams AU - Chin-Fang Lin AU - Elliot S. Friedman AU - Phyllis A. Gimotty AU - Gary D. Wu AU - Laura F. Su TI - SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens AID - 10.1101/2021.11.29.470421 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.11.29.470421 4099 - http://biorxiv.org/content/early/2021/11/30/2021.11.29.470421.short 4100 - http://biorxiv.org/content/early/2021/11/30/2021.11.29.470421.full AB - The baseline composition of T cells directly impacts later response to a pathogen, 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, including memory cells with gut homing receptors. T cell clones generated from tetramer-labeled cells cross-reacted with bacterial peptides and responded to stool lysates in a MHC-dependent manner. Integrated phenotypic analyses revealed additional precursor diversity that included T cells with distinct polarized states and trafficking potential to other barrier tissues. Our findings illustrate a complex pre-existing memory pool poised for immunologic challenges and implicate non-infectious stimuli from commensal colonization as a factor that shapes pre-existing immunity.One Sentence Summary Pre-existing immunity to SARS-CoV-2 contains a complex pool of precursor lymphocytes that include differentiated cells with broad tissue tropism and the potential to cross-react with commensal antigens.Competing Interest StatementThe authors have declared no competing interest.