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