Human thymopoiesis produces polyspecific CD8+ α/β T cells responding to multiple viral antigens
Valentin Quiniou, Pierre Barennes, Vanessa Mhanna, Paul Stys, Hélène Vantomme, Zhicheng Zhou, Federica Martina, Nicolas Coatnoan, Michele Barbie, Hang‐Phuong Pham, Béatrice Clemenceau, Henri Vié, Mikhail Shugay, Adrien Six, Barbara Brandao, Roberto Mallone, Encarnita Mariotti‐Ferrandiz, David Klatzmann
Abstract
T-cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating >10 19 sequences. They are selected during thymopoiesis, which releases a repertoire of about 10 8 unique TCRs per individual. How evolution shaped a process that produces TCRs that 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. Expansion of such rare T cells would provide enough fighters for an effective immune response and enough antigen-experienced cells for memory. We show here that human thymopoiesis releases a large population of clustered CD8 + T cells harboring α/β paired TCRs that (i) have high generation probabilities and (ii) a preferential usage of some V and J genes, (iii) which CDR3 are shared between individuals, and (iv) can each bind and be activated by multiple unrelated viral peptides, notably from EBV, CMV, and influenza. These polyspecific T cells may represent a first line of defense that is mobilized in response to infections before a more specific response subsequently ensures viral elimination. Our results support an evolutionary selection of polyspecific α/β TCRs for broad antiviral responses and heterologous immunity.