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April 30, 2023

Human thymopoiesis produces polyspecific CD8+ α/β T cells responding to multiple viral antigens

eLife - 2023



Valentin Quiniou, Pierre Barennes, Vanessa Mhanna, Paul Stys, Helene Vantomme, Zhicheng Zhou, Federica Martina, Nicolas Coatnoan, Michele Barbie, Hang-Phuong Pham, Béatrice Clémenceau, Henri Vie, Mikhail Shugay, Adrien Six, Barbara Brandao, Roberto Mallone, Encarnita Mariotti-Ferrandiz, David Klatzmann.

  • puce

    T-cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating >1019 sequences. They are selected during thymopoiesis, which releases a repertoire of about 108 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.

  • puce

    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.

  • puce

    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.

  • puce

    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.

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