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⁺ 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. [ABSTRACT FROM AUTHOR]