Intraclonal competition limits the fate determination of regulatory T cells in the thymus

Abstract

Because the deletion of self-reactive T cells is incomplete, thymic development of natural Foxp3+CD4+ regulatory T (Treg) cells is required for preventing autoimmunity. However, the role of T cell receptor (TCR) specificity in thymic Treg cell development remains controversial. To address this issue, we generated a transgenic line expressing a naturally occurring Treg cell-derived TCR. Surprisingly, efficient thymic Treg cell development occurred only when the antigen-specific Treg cell precursors were present at low clonal frequency (<1%) within a normal thymus. Using retroviral vectors and bone marrow chimeras, we observed similar behavior with two other Treg cell-derived TCRs. These data demonstrate that thymic Treg cell development is a TCR-instructive process involving a niche which can be saturable at much lower clonal frequencies than the niche for positive selection.

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

“…On the one hand, antigen-unspecific environmental cues have a role, as T reg differentiation is known to segregate into a TCR-driven instructive phase and a cytokine-dependent 'consolidation' phase ('two-step model') 43 . On the other hand, intraclonal competition, possibly caused by limited access to antigen, restricts the number of clonal precursors that actually enter the T reg lineage [44][45] . In this context, it is intriguing to note that the presentation of certain PTAs, due to stochastic fluctuations in 'promiscuous' gene expression, may be restricted to a very limited number of stromal APCs [46][47] .…”

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

“…These results indicate that TCR specificity to self-Ags is not the sole determinant to discriminate CD4/CD8 lineage choice in the Thpok DTE/DTE setting. Supposing that the number of thymic epithelial cells presenting natural selective ligands to transgenic TCR is limited, it is possible that intraclonal competition within the postselection thymocyte population takes place when they all express identical TCR, as was reported during differentiation of regulatory T cells (15). A small proportion of postselection thymocytes that are losers in this competition might receive shorter TCR signals than do the winners.…”

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

“…21,22 Separate signals? Downstream signals, pERK and Ca 2C flux, in regards to the zipper model that mediate Treg formation need to be addressed.…”

“…20 Clonal deletion, elimination of TCRs that present with high affinity to self peptide, and clonal diversion, conversion of moderate to high affinity TCRs to regulatory T cell (Tregs) lineage are the key processes that impact central tolerance. 21,22 Events that lead to central tolerance are key to the development of TCRs for adoptive cell therapy.…”