FOXP3

Official Full Name

forkhead box P3

Organism

Homo sapiens

GeneID

50943

Background

The protein encoded by this gene is a member of the forkhead/winged-helix family of transcriptional regulators. Defects in this gene are the cause of immunodeficiency polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Synonyms

JM2; AIID; IPEX; PIDX; XPID; DIETER;

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Detailed Information

Foxp3, as a transcription factor, is predominantly expressed in CD4⁺CD25⁺ Treg cells and is a master regulator for the development and function of Treg cells. Foxp3-mutant scurfy mice and Foxp3-deficient mice displayed lethal autoimmune lymphoproliferative disease, which results from a defection of CD4⁺CD25⁺ Treg cells. Similarly, mutations of FOXP3 gene in human are responsible for severe autoimmune disease, called IPEX syndrome (Immune dysfunction/Polyendocrinopathy/Enteropathy/X-linked syndrome). Dramatically, when Foxp3 was ectopically expressed through retroviral gene transfer, non-Treg cells in mice and in human acquired a Treg cell phenotype similar to that of naturally occurring Treg cells. Moreover, stable Foxp3 expression is clearly a prerequisite for the maintenance of the transcriptional and functional program established during Treg cell development. Because deletion of Foxp3, in mature Treg cells, led to the loss of their suppressive function in vivo. Exactly, Foxp3 amplifies and fixes pre-established molecular features of Treg cells, and solidifies Treg cell lineage stability.

The cis-acting elements of Foxp3 gene

The study by Mantel et al. showed an initial characterization of the human FOXP3 promoter, which is located 6.5 kb upstream of the first exon, containing six NFAT and AP-1 binding sites and a TATA and CAAT box. The promoter is highly conserved between humans, rats, and mice. In addition to having a conserved promoter region, the Foxp3 locus contains three proximal intronic conserved non-coding DNA sequence (CNS) elements, CNS1, CNS2, and CNS3 (Figure 1). CNS1, a intronic enhancer (enhancer 1), contains the TGF-β-responsive element and binding sites for transcription factors, such as NFAT and Smad, and is involved in TGF-β-induced Foxp3 expression in induced Tregs (iTregs) cells. Although it was showed that CNS1 is redundant for natural Tregs (nTregs) cell differentiation, but it has a prominent role in iTreg cell generation in gut-associated lymphoid tissues. CNS2, corresponding to the TCR-responsive enhancer (enhancer 2), contains a CpG island and binding sites for transcription factors, such as CREB and STAT5. It was showed that CNS2 is required for Foxp3 expression in the mature nTreg cells. Worthy of note, CNS3 that acts as a pioneer element has an important role in generation of Treg cells in the thymus and the periphery. There are also binding sites for transcription factors, such as c-Rel, in CNS3.

Figure 1. Signaling pathways, transcription factors and structure of the murine Foxp3 gene.

Foxp3 and Autoimmune Diseases

Under normal physiological conditions, Foxp3 determines the number and function of Tregs and maintains normal immune balance by regulating gene and protein levels. In the pathological conditions seen in autoimmune disease, changes in environmental stimuli affect the expression and stability of Foxp3 and thus affect differentiation, hyperplasia, and the immunosuppressive function of Tregs. SLE is an inflammatory autoimmune disease. Inflammatory cytokines IL-1β, IL-6, IL-12, IL-17, and TNF-α are elevated in the peripheral blood and a majority of them are associated with disease activity. These inflammatory cytokines can influence Treg function by influencing the stability of Foxp3 by different signaling pathways. IL-1β downregulates TGF-β-induced Foxp3 expression and TNF-α activates protein phosphatase 1 dephosphorylation of the Ser418 site of Foxp3, both possibly receding Treg cell suppressive function. Inflammatory cytokines can also modulate regulatory T cell development by nuclear factor-κB directly regulating expression of the Foxp3 transcription factor. The effects of proinflammatory cytokines on Foxp3 can be felt at numerous levels of gene expression regulation. IL-6 restrains Treg differentiation, which is a significant mechanism involved in the pathogenesis of SLE.

FOXP3 Expression and Prognosis in Human Cancer

In sharp contrast to a putative onco-suppressor role for FOXP3, emerging evidence from studies of human cancer samples points to its pro-metastatic action in vivo, based on the correlation between FOXP3 expression by tumor cells and poor prognosis. Moreover, recent data show that FOXP3 is expressed in carcinoma cells in all cancer types except in ovarian carcinoma; in fact, FOXP3 expression was readily detected immunohistochemically in ovarian epithelium from healthy women, whereas no or weak expression was detected in tumor cells. In prostatic epithelial cells, FOXP3 nuclear staining was observed in all samples of normal and of benign prostate tissues tested but also in 30% of prostate cancer samples. Recent studies have suggested a role for FOXP3 in tumor dissemination to distant organs. For instance, the immunohistochemical analysis of archival samples from human breast cancer patients detected FOXP3 expression in 66% of the samples and identified FOXP3 expression in tumor cells as an independent strong prognostic factor for distant metastases, but not for local recurrence risk. Furthermore, multivariate analysis revealed a similar hazard ratio for FOXP3 expression and lymph node positivity.

References:

Tao J H, et al. Foxp3, Regulatory T Cell, and Autoimmune Diseases. Inflammation, 2016, 40(1):1-12.
Maruyama T, et al. The molecular mechanisms of Foxp3 gene regulation. Seminars in Immunology, 2011, 23(6):0-423.
Haiqi H, et al. Transcriptional regulation of Foxp3 in regulatory T cells. Immunobiology, 2011, 216(6):0-685.
TRIULZI T, et al. FOXP3 expression in tumor cells and implications for cancer progression. Journal of Cellular Physiology, 2013, 228(1):30-35.

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