Human thymopoiesis selects unconventional CD8+ α/β T cells that respond to multiple viruses

T cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating ≫10 sequences. They are selected during thymopoiesis, which releases a repertoire of about 10 unique TCRs per individual. How evolution shaped a process that produces TCRs that would effectively respond to 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. Expansion of such rare T cells would provide enough fighters for an efficacious immune response and enough antigen-experienced cells for memory. We show here that thymopoiesis releases a large population of CD8 T cells harbouring diverse α/βTCRs with innate-like properties. These TCRs (i) have high generation probabilities and a preferential usage of some V and J genes, (ii) are shared between individuals, (iii) are highly enriched for viral antigen recognition and (iv) have a fuzzy rather than tight specificity. In vitro, T cells expressing these TCRs bind to and are activated by multiple unrelated viral peptides; in vivo, they respond to vaccination and infection, being notably found in bronchoalveolar lavages of COVID-19 infected patients. Our results support an evolutionary selection of pleiospecific α/βTCRs for broad antiviral responses and heterologous immunity.