Abstract
The discovery of FOXP3(+) regulatory T (T(reg)) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in T(reg) cell lineage determination and maintenance, but is not sufficient to enable the full potential of T(reg) cell suppression, indicating that other factors orchestrate the fine-tuning of T(reg) cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to T(reg) cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree T(reg) cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of T(reg) cells in the periphery and the multilayered mechanisms by which T(reg) cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of T(reg) cells in humans and mice. Further, we examine evidence for T(reg) cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.