The regulation of immune tolerance by FOXP3

Key Points Forkhead box protein P3 (FOXP3) is a crucial regulator of regulatory T (T reg ) cell gene expression that is responsible for much of the suppressive potential displayed by these cells. The regulation of FOXP3 expression in T reg cells occurs through the concerted action of transcription factors and extensive epigenetic control mechanisms; furthermore, post-translational modifications are also capable of modulating FOXP3 function. These several layers of FOXP3 control are responsive to positive and negative regulation by factors in the tissue environment, including cytokines, inflammatory mediators and metabolic factors. Modulating FOXP3 expression and T reg cell function by targeting newly discovered regulatory nodes may lead to the development of new immunotherapies for cancer and autoimmune diseases. This Review considers how forkhead box protein P3 (FOXP3) — the key transcription factor of regulatory T (T reg ) cells — is regulated both at the transcriptional level and through post-translational modifications. The authors explain how FOXP3 interacts with other molecules to induce and maintain T reg cell populations, and they discuss the potential of therapeutically targeting FOXP3 in the context of human disease. The proper restraint of the destructive potential of the immune system is essential for maintaining health. Regulatory T (T reg ) cells ensure immune homeostasis through their defining ability to suppress the activation and function of other leukocytes. The expression of the transcription factor forkhead box protein P3 (FOXP3) is a well-recognized characteristic of T reg cells, and FOXP3 is centrally involved in the establishment and maintenance of the T reg cell phenotype. In this Review, we summarize how the expression and activity of FOXP3 are regulated across multiple layers by diverse factors. The therapeutic implications of these topics for cancer and autoimmunity are also discussed.