FOXP3

The human FOXP3 genes contain 11 coding exons. Exon-intron boundaries are identical across the coding regions of the mouse and human genes. By genomic sequence analysis, the FOXP3 gene maps to the p arm of the X chromosome (specifically, Xp11.23). == Identification ==

A 2001 Nature Genetics paper identified the scurfy gene product, initially termed scurfin and later known as FOXP3, linking its disruption to a fatal lymphoproliferative disorder in mice. == Physiology ==

FOXP3 is a specific marker of natural T regulatory cells (nTregs, a lineage of T cells) and adaptive/induced T regulatory cells (a/iTregs), also identified by other less specific markers such as CD25 or CD45RB. The induction or administration of FOXP3 positive T cells has, in animal studies, led to marked reductions in (autoimmune) disease severity in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease. Human trials using regulatory T cells to treat graft-versus-host disease have shown efficacy. Further work has shown that T cells are more plastic in nature than originally thought. This means that the use of regulatory T cells in therapy may be risky, as the T regulatory cell transferred to the patient may change into T helper 17 (Th17) cells, which are pro-inflammatory rather than regulatory cells. CD4+ cells are leukocytes responsible for protecting animals from foreign invaders such as bacteria and viruses. Defects in this gene's ability to function can cause IPEX syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome as well as numerous cancers. While CD4+ cells are heavily regulated and require multiple transcription factors such as STAT-5 and AhR in order to become active and function properly, FOXP3 has been identified as the master regulator for Treg lineage. FOXP3 can either act as a transcriptional activator or suppressor depending on what regulators such as deacetylases and histone acetylases are acting on it. The FOXP3 gene is also known to convert naïve T-cells to Treg cells, which are capable of in vivo and in vitro suppressive capabilities suggesting that FOXP3 is capable of regulating the expression of suppression-mediating molecules. Clarifying the gene targets of FOXP3 could be crucial to the comprehension of the suppressive abilities of Treg cells. == Pathophysiology ==

In human disease, alterations in numbers of regulatory T cellsand in particular those that express FOXP3are found in a number of disease states. For example, patients with tumors have a local relative excess of FOXP3 positive T cells which inhibits the body's ability to suppress the formation of cancerous cells. Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of FOXP3 positive cells. The FOXP3 gene is also mutated in IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked). Many patients with IPEX have mutations in the DNA-binding forkhead domain of FOXP3. In mice, a FOXP3 mutation (a frameshift mutation that result in protein lacking the forkhead domain) is responsible for 'Scurfy', an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth. These mice have overproliferation of CD4+ T-lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines. This phenotype is similar to those that lack expression of CTLA-4, TGF-β, human disease IPEX, or deletion of the FOXP3 gene in mice ("scurfy mice"). The pathology observed in scurfy mice seems to result from an inability to properly regulate CD4+ T-cell activity. In mice overexpressing the FOXP3 gene, fewer T cells are observed. The remaining T cells have poor proliferative and cytolytic responses and poor interleukin-2 production, although thymic development appears normal. Histologic analysis indicates that peripheral lymphoid organs, particularly lymph nodes, lack the proper number of cells. == Role in cancer ==

In addition to FOXP3's role in regulatory T cell differentiation, multiple lines of evidence have indicated that FOXP3 play important roles in cancer development. Down-regulation of FOXP3 expression has been reported in tumour specimens derived from breast, prostate, and ovarian cancer patients, indicating that FOXP3 is a potential tumour suppressor gene. Expression of FOXP3 was also detected in tumour specimens derived from additional cancer types, including pancreatic, melanoma, liver, bladder, thyroid, cervical cancers. However, in these reports, no corresponding normal tissues were analyzed, therefore it remained unclear whether FOXP3 is a pro- or anti-tumourigeneic molecule in these tumours. Two lines of functional evidence strongly supported that FOXP3 serves as a tumour suppressive transcription factor in cancer development. First, FOXP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of FOXP3 in melanoma, glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies. FOXP3 is a recruiter of other anti-tumor enzymes such as CD39 and CD8. In one experiment a 15-mer synthetic peptide, P60, was able to inhibit FOXP3's ability to function. P60 did this by entering the cells and then binding to FOXP3, where it hinders FOXP3's ability to translocate to the nucleus. Due to this, FOXP3 could no longer properly suppress the transcription factors NF-kB and NFAT; both of which are protein complexes that regulate transcription of DNA, cytokine production and cell survival. This would inhibit a cell's ability to perform apoptosis and stop its own cell cycle, which could potentially allow an affected cancerous cell to survive and reproduce. == Autoimmune ==

Mutations or disruptions of the FOXP3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus. It does this by recruiting CD39, a rate-limiting enzyme that's vital in tumor suppression to hydrolyze ATP to ADP in order to regulate immunosuppression on different cell populations. == See also ==