The checkpoint for agonist selection precedes conventional selection in human thymus

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(+) CD8 alpha alpha(+) subset of mature CD8 alpha alpha T cells that displays an effector phenotype associated with agonist selection. TCR stimulation of immature post-a-selection thymocyte blasts specifically gives rise to this innate subset and fixes early T cell receptor alpha variable (TRAY) 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