The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases

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.