Ubiquitous points of control over regulatory T cells

Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins involved in processes including DNA repair, cell cycle progression, protein quality control, and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. Now it is clear that the activities of molecules and pathways central to immune regulation are also modified and controlled by ubiquitin tagging. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on the signaling pathways pertinent to these cells or through the direct, posttranslational regulation of Foxp3. In this review, we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of Treg biology including the generation, function and phenotypic fidelity of these cells. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine-tuning of immune restraint.