Abstract
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.
Highlights
T cells are one of the major components of the adaptive immune system which protects against all kind of pathogens, harmful substances, and foreign tissues
We found that only ∼1% of mature tTregs lost Foxp3 expression in secondary lymphoid organs, indicating that tTregs are stable under homeostatic conditions
We further demonstrated that the signal switch from IL-2 to ICOS/PI3K during Treg activation account for Foxp3 instability and Treg reprogramming [12]
Summary
T cells are one of the major components of the adaptive immune system which protects against all kind of pathogens, harmful substances, and foreign tissues. Sustained Foxp3 expression in mature Tregs is critical for maintaining of the Treg cell identity and suppression of life-threatening autoimmunity [8]. The metabolic status during tTreg cell activation and environmental cytokine cues contribute to the stability of Foxp3 expression [44,45,46,47,48,49].
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