Foxp3 positive regulatory T cells: a functional regulation by the E3 ubiquitin ligase Itch

Regulatory T cells (Tregs) play a critical role in maintaining immune tolerance to self-antigens, whose development and activation is controlled by the master regulator and transcription factor Foxp3. Foxp3 acts as transcription repressor and exerts its suppressing function via directly associating with and inhibiting the function of other transcriptional regulators. The gene transcription of Foxp3 is regulated by diverse mechanisms at the cellular and molecular levels including the pleiotropic cytokine transforming growth factor-beta (TGF-beta). Itch is an E3 ubiquitin ligase whose deficiency is linked to excessive immune responses, abnormal T helper cell differentiation, and failed T cell anergy induction. Recent evidence indicates that Itch is involved in TGF-beta-induced Foxp3 expression and Treg-regulated airway inflammation, thus identifying a ubiquitin-dependent pathway in modulating Tregs.