The checkpoint for agonist selection precedes conventional selection in human thymus

Abstract

The thymus plays a central role in self-tolerance, in part 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. Interestingly, TCR stimulation of immature post-β-selection thymocyte blasts specifically gives rise to this innate subset and fixes early TRAV and TRAJ rearrangements in the TCR repertoire. These findings suggest that the checkpoint for agonist selection precedes conventional selection in human thymus.

αβ T‐cell receptors with a central CDR3 cysteine are enriched in CD8αα intraepithelial lymphocytes and their thymic precursors

“…10 Human IEL precursor thymocytes (IELp) express TCRa chains that use more proximal Trav and Traj gene segments than CD8 + na€ ıve T cells. 11 As both populations express diverse Trav and Traj gene segments, this finding reveals a difference in the time spent as a pre-selection thymocyte rather than a difference in TCR-intrinsic motifs of IELp versus CD8 + na€ ıve T cells.…”

“…In pre‐selection thymocytes the TCRα chain is altered via recombination events that are thought to incorporate TCRα V ( Trav ) and TCRα J ( Traj ) segments located progressively further away from the junction of the Trav and Traj loci . Human IEL precursor thymocytes (IELp) express TCRα chains that use more proximal Trav and Traj gene segments than CD8 + naïve T cells . As both populations express diverse Trav and Traj gene segments, this finding reveals a difference in the time spent as a pre‐selection thymocyte rather than a difference in TCR‐intrinsic motifs of IELp versus CD8 + naïve T cells.…”

Diverse developmental pathways of intestinal intraepithelial lymphocytes

“…However, a recent report provided some evidence that these cells avoided detection because they express both CD8αα and CD8αβ co-receptors 68 . The development and function of human CD8αα + TCRαβ + IELs and their relationship to mouse unconventional TCRαβ + IELs need further study.…”

Human intraepithelial lymphocytes

“…The existence of this population in human has been speculated on 29 based on misinterpretation of data that failed to exclude TCRγδ + IEL, which can express CD8αα, from the analysis 14 , 35 . Additionally, a recent report showing a TCRαβ + CD8α + /CD8β-dim population in human intestine 36 attempted to extend this observation to suggest the existence of TCRαβ + CD8αα + IEL in human; however, the data suggests the same cell may express both CD8αα and CD8αβ dimers, a cell type that would not phenocopy the bonafide TCRαβ + CD8αα + IEL found in mouse. Finally, the TCRαβ + CD8/CD4 double negative population which is enriched in the mouse colon 30 , 32 and considered to be similar in nature to TCRαβ + CD8αα + IEL 37 , 38 as well as the TCRαβ + CD4 + CD8α + IEL 39 whose inflammatory potential is modulated in the intestine via the upregulation of Runx3 and downregulation of ThPOK 40 , 41 are both still poorly characterized in human.…”

“…Conversely, induction of the CD8αα homodimer on TCRαβ + CD8αβ + IEL in mouse is thought to increase the TCR activation threshold 79 . Such a function for the CD8αα homodimer based on the observation of a TCRαβ + CD8α + /CD8β-dim population in human intestine 36 is possible but yet to be demonstrated. The ability to recognize self-antigens is further enhanced when IL-15, 81 a cytokine induced under conditions of stress, inflammation and infection, is upregulated 80 , 82 , 83 .…”