%0 Journal Article %A Verstichel, Greet %A Vermijlen, David %A Martens, Liesbet %A Goetgeluk, Glenn %A Brouwer, Margreet %A Thiault, Nicolas %A Van Caeneghem, Yasmine %A De Munter, Stijn %A Weening, Karin %A Bonte, Sarah %A Leclercq, Georges %A Taghon, Tom %A Kerre, Tessa %A Saeys, Yvan %A Van Dorpe, Jo %A Cheroutre, Hilde %A Vandekerckhove, Bart %T The checkpoint for agonist selection precedes conventional selection in human thymus %D 2017 %R 10.1126/sciimmunol.aah4232 %J Science Immunology %P eaah4232 %V 2 %N 8 %X T cells walk a tight rope in fighting infection without harming the body—They respond to foreign antigens in the context of self-MHC without reacting so strongly that they attack self. Conventional T cells achieve this balance through positive and negative selection in the thymus. Verstichel et al. report that agonist-selected T cells in humans undergo a different process. A PD-1 T cell population acquired features of tissue-resident effector cells and an innate functional effector phenotype in response to self-antigen in the thymus. Immature thymocytes were diverted to this agonist selection pathway before conventional selection. This timing suggests that, rather than being by-products of failed negative selection, these cells instead follow a distinct path to survive thymic selection.The thymus plays a central role in self-tolerance, partly by eliminating precursors with a T cell receptor (TCR) that binds strongly to self-antigens. However, the generation of self-agonist–selected lineages also relies on strong TCR signaling. How thymocytes discriminate between these opposite outcomes remains elusive. Here, we identified a human agonist–selected PD-1+ CD8αα+ subset of mature CD8αβ+ T cells that displays an effector phenotype associated with agonist selection. TCR stimulation of immature post–β-selection thymocyte blasts specifically gives rise to this innate subset and fixes early T cell receptor alpha variable (TRAV) and T cell receptor alpha joining (TRAJ) rearrangements in the TCR repertoire. These findings suggest that the checkpoint for agonist selection precedes conventional selection in the human thymus. %U https://immunology.sciencemag.org/content/immunology/2/8/eaah4232.full.pdf