Polyspecific CD8+ alpha/beta T-cells that respond to multiple viruses and drive COVID-19 outcome

Randomly generated T cell receptors (TCRs) selected during thymopoiesis form a repertoire of about 108 unique TCRs per individual. How these diverse TCRs can effectively handle a countless and evolving set of infectious agents is a central question of immunology. The paradigm is that a diverse enough repertoire of TCRs should always provide a proper, though rare, specificity for any given need. We analyzed the generation and use of TCR in humans using deep and single-cell sequencing. We found that thymopoiesis releases a large population of CD8+ T cells harboring diverse and polyspecific alpha and beta TCRs that can each recognize and respond to multiple unrelated viral peptides, notably from EBV, CMV and influenza. These TCRs participate in a first-line response to vaccination and infection, including to SARS-CoV-2 for which they predict the infection outcome. Our results support an evolutionary selection of polyspecific alpha and betaTCRs for broad antiviral responses and heterologous immunity.