Foxp3 Instability Helps tTregs Distinguish Self and Non-self

Regulatory T cells (Tregs) are small subsets of CD4 T cells that play a central role in the controlling of immune tolerance. Tregs are either generated in the thymus (tTregs) or the periphery (pTregs), and both express the master transcription factor Foxp3. Stable expression of Foxp3 is important for the maintenance of Tregs identity and their suppressive function. Similar to conventional T cells, Tregs can recognize both self- and non-self-antigens, and TCR engagement leads to Treg activation and the generation of effector Tregs. Emerging shreds of evidence suggest Tregs are not always stable, even fully committed mature tTregs, and can lose foxp3 expression and programming to effector-like T cells. In this review, we summarize recent findings in Treg instability and the intrinsic and extrinsic mechanisms in controlling the Foxp3 expression. Finally, we propose a new hypothesis that Foxp3 instability might help tTregs distinguish between self and non-self-antigens.