Regulation of Treg Functions by the Ubiquitin Pathway

Regulatory T (Tregs) cells, required to maintain immune homeostasis, have significant power in disease outcomes. Treg dysfunction, predominantly characterized by the loss of the master transcription factor FoxP3 and the acquisition of T_eff-like phenotypes, can promote autoimmunity as well as enhance anti-tumor immunity. As FoxP3 expression and stability are pinnacle for Treg suppressive functions, understanding the pathways that regulate FoxP3 is crucial to ascertain Treg-mediated therapies for autoimmune diseases and cancer. Mechanisms controlling FoxP3 expression and stability range from transcriptional to posttranslational, revealing multiple therapeutic opportunities. While many of the transcriptional pathways have been explored in detail, a recent surge in interest on the posttranslational mechanisms regulating FoxP3 has arisen. Particularly, the role of ubiquitination on Tregs both directly and indirectly involving FoxP3 has gained interest. Here, we summarize the current knowledge on ubiquitin-dependent, FoxP3-mediated control of Treg function as it pertains to human diseases.