The checkpoint for agonist selection precedes conventional selection in human thymus

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Science Immunology  24 Feb 2017:
Vol. 2, Issue 8, eaah4232
DOI: 10.1126/sciimmunol.aah4232

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Surviving selection

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.

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