Ubiquitous points of control over regulatory T cells

Abstract

Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins and 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. It is now clear that the activities of molecules and pathways central to immune regulation are also modified and regulated through ubiquitin. 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 signaling pathways pertinent for 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 biology of Tregs including their generation, function and phenotypic fidelity. 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.

Missed, Not Missing: Phylogenomic Evidence for the Existence of Avian FoxP3

“…A deeper understanding of the molecular determinants of Tregs in avian species will facilitate the therapeutic manipulation of these cells. As a major transcriptional factor in the transcriptomic landscape of mammalian Tregs, FoxP3 is an obvious target for small molecule, antibody and chimeric therapies of the future [ 59 – 63 ]. Demonstration of the impact of FoxP3 in avian Tregs would pave the way for a raft of new therapies for diseases that not only impose a significant welfare burden, but also costs the global poultry industry millions of dollars in lost revenue [ 64 – 67 ].…”

Physiological, Tumor, and Metastatic Niches: Opportunities and Challenges for Targeting the Tumor Microenvironment

“…Tregs are characterized by their expression of CD4, CD25 and FoxP3, the latter of which is a key transcription factor for the development of Tregs and their immunnosuppressive capabilities. 66 Two main subsets of Tregs have been identified, including natural Tregs, which are produced in the thymus, and adaptive Tregs, which are induced from naïve T cells in the periphery in response to chronic exposure to antigen. Induced Tregs are prominent in the tumor microenvironment, where they expand in response to VEGF, CXCL12, IL-10, and TGF-β and are capable of producing a number of immunosuppressive signals, including adenosine and prostaglandin E 2 .…”

T Regulatory Cells From Non-obese Diabetic Mice Show Low Responsiveness to IL-2 Stimulation and Exhibit Differential Expression of Anergy-Related and Ubiquitination Factors

“…Recently, it has been demonstrated that Foxp3 maintenance is also affected by inflammatory cytokines and other factors, which alter post-translational modifications such as ubiquitination, acetylation, and phosphorylation thus regulating the stability of the cellular pools of Foxp3 (14). Indeed, Foxp3 stability has been linked to the activities of the deubiquitinase USP7 and ubiquitinase STUB1, which respectively avoid or promote Foxp3 proteasome degradation (15, 16). Thus, in addition to the transcriptional control of foxp3 expression, other mechanisms of regulation contribute to the overall abundance and activity of Foxp3, affecting the functions of Tregs and therefore the maintenance of self-tolerance.…”