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The regulation of immune tolerance by FOXP3

Key Points

  • Forkhead box protein P3 (FOXP3) is a crucial regulator of regulatory T (Treg) cell gene expression that is responsible for much of the suppressive potential displayed by these cells.

  • The regulation of FOXP3 expression in Treg 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 Treg cell function by targeting newly discovered regulatory nodes may lead to the development of new immunotherapies for cancer and autoimmune diseases.

Abstract

The proper restraint of the destructive potential of the immune system is essential for maintaining health. Regulatory T (Treg) 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 Treg cells, and FOXP3 is centrally involved in the establishment and maintenance of the Treg 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.

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Figure 1: The control of forkhead box protein P3 expression by transcription factors and regulatory elements within the FOXP3 gene locus.
Figure 2: Environmental cues modulate the transcription, stability and function of forkhead box protein P3.
Figure 3: Post-translational modifications of forkhead box protein P3 and their impact on regulatory T cell function.

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Acknowledgements

The laboratory of F.P. is supported by grants from the Bloomberg–Kimmel Institute of Johns Hopkins University (Maryland, USA), the US National Institutes of Health (grants RO1AI099300 and RO1AI089830) and the US Department of Defense (grant PC130767). F.P. is the recipient of an Established Investigator Award from the Melanoma Research Alliance (Washington, USA). The research of J.B. is supported by a grant from the Roswell Park Alliance Foundation and by the US National Cancer Institute (grant P30CA016056). The laboratory of L.L. is supported by the National Natural Science Fund of China (grants 81571564 and 81522020), the 863 Young Scientists Special Fund (grant SS2015AA020932) and the Natural Science Foundation of China (grant 91442117). The authors thank S. Newman, A. Lebid, X. Ni, P. Wei and A. Ramaswamy for help with preparing the figures and for critically reviewing the manuscript.

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Correspondence to Ling Lu, Joseph Barbi or Fan Pan.

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Lu, L., Barbi, J. & Pan, F. The regulation of immune tolerance by FOXP3. Nat Rev Immunol 17, 703–717 (2017). https://doi.org/10.1038/nri.2017.75

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