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 α/βTCRs 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 α/βTCRs for broad antiviral responses and heterologous immunity.Funding: This work was primarily funded by the TRiPoD ERC-Advanced EU (322856) grant to DK.The LabEx Transimmunom (ANR-11-IDEX-0004-02) and RHU iMAP (ANR-16-RHUS-0001) grants also contributed.Conflict of Interest: The authors declare no competing financial interests.Ethical Approval: Thirteen human thymus samples were obtained from organ donors undergoing surgery (Department of Cardiac Surgery, Pitié-Salpêtrière Hospital, France) after approval by the Agence de Biomédecine and the Ministry of Research.
Polyspecific CD8+ α/βT-Cells that Respond to Multiple Viruses and Drive COVID-19 Outcome