The regulation of immune tolerance by FOXP3

Abstract

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.

Figure 1. The control of forkhead box protein P3 expression by transcription factors and regulatory elements within the FOXP3 gene locus

The figure depicts the characterized coding and non-coding elements of the gene that encodes forkhead box protein P3 (FOXP3) along with the transcription factors that are reported to activate the transcription of the gene and their sites of interaction. Transcription factors that bind to the promoter, conserved non-coding sequence 1 (CNS1), CNS2 and CNS3 regions of FOXP3 are shown in blue, red, green and yellow, respectively. Also depicted are the CNS2-targeting methylating enzyme DNA methyltransferase 1 (DNMT1) and the demethylating enzyme ten-eleven translocation 1 (TET1), which influence the inactive and active transcriptional status of that region, respectively. ATF1, activating transcription factor 1; CBFβ, core-binding factor subunit-β; CREB, cAMP-responsive element-binding protein; FOXO, forkhead box protein O; iT_reg, in vitro-induced regulatory T; NFAT, nuclear factor of activated T cells; pT_reg, peripherally derived regulatory T; RAR, retinoic acid receptor; RUNX1, Runt-related transcription factor 1; RXR, retinoid X receptor; STAT5, signal transducer and activator of transcription 5; tT_reg, thymus-derived regulatory T.

Figure 2. Environmental cues modulate the transcription, stability and function of forkhead box protein P3

The induction and maintenance of forkhead box protein P3 (FOXP3) transcription can be positively influenced by cytokines such as transforming growth factor-β (TGFβ) and interleukin-2 (IL-2), and by other factors in the tissue microenvironment, such as retinoic acid, vitamin C and short-chain fatty acids (SCFAs). By contrast, FOXP3 is negatively regulated by pro-inflammatory cytokines, such as tumour necrosis factor (TNF) and IL-6, and by other factors, such as Toll-like receptor (TLR) activation or robust T cell receptor (TCR) and co-stimulatory molecule signalling. These factors can alter the post-translational modifications that are made to the mature FOXP3 protein to either stabilize or deplete the cellular pools of FOXP3 and modulate its functional capacity. By affecting FOXP3 expression and function, these factors influence the many functions of regulatory T (T_reg) cells, such as their production of anti-inflammatory cytokines, their modulation of antigen-presenting cell (APC) function, their consumption of growth factors and their ability to induce apoptosis in effector immune cells. ATRA, all-trans-retinoic acid; CNS, conserved non-coding sequence; CTLA4, cytotoxic T lymphocyte antigen 4; DNMT1, DNA methyltransferase 1; FOXO, forkhead box protein O; IL-2R, IL-2 receptor; LAG3, lymphocyte activation gene 3 protein; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; PP1, protein phosphatase 1; STAT, signal transducer and activator of transcription; TET, ten-eleven translocation; TGFβR, TGFβ receptor; USP7, ubiquitin-specific peptidase 7.

Figure 3. Post-translational modifications of forkhead box protein P3 and their impact on regulatory T cell function

Depicted on the left is a schematic representation of the mature forkhead box protein P3 (FOXP3) molecule showing its functional domains and reported post-translational modification sites. The table on the right summarizes the types of modification that can occur in each region of FOXP3, the effects of these modifications on FOXP3 protein stability and function, and the subsequent impact on the suppressive function of regulatory T (T_reg) cells. CDK2, cyclin-dependent kinase 2; PP1, protein phosphatase 1; SIRT1, sirtuin 1; USP7, ubiquitin-specific peptidase 7.