FOXP3 (forkhead box P3), also known as scurfin.
The FOXP3 genes contain 11 coding exons.
FOXP3 is a protein involved in immune system responses.
It is a member of the FOX protein family.
The FOXP3 gene functions as a master regulator of the regulatory pathway in the development and function of regulatory T cells.
FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, and may inhibit transcription of key genes following stimulation of T cell receptors.
FOXP3 is a member of the FKH family of transcription factors and contains a proline‐rich (PRR) amino‐terminal domain, central zinc finger (ZF) and leucine zipper (LZ) domains important for protein–protein interactions, and a carboxyl‐terminal FKH domain required for nuclear localization and DNA‐binding activity.
A consequence of malfunctioning FOXP3 expression leads to a defect in Treg production.
Those patients do not have circulating CD4+/CD25+/FOXP3+ Treg cells.
Regulatory T cells generally downgrade the immune response down.
Therefore an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells.
In autoimmune disease, a deficiency of regulatory T cell activity allows other autoimmune cells to attack the body’s own tissues.
FOXP3’s gene location is on the X chromosome.
FOXP3 gene maps to the p arm of the X chromosome (specifically, Xp11.23).
FOX proteins, the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription.
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.
FOXP3 expression is characterized by controlling transcription, influencing epigenetic and post-transcriptional modifications.
FOXP3 can change transcription or epigenetic regulation of Treg cells.
FOXP3 is important in the regulation of transcriptional activity/repression in Treg cells.
Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-tolerance.
Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-tolerance.
The induction or administration of Foxp3 positive T cells has, in animal studies, led to marked reductions in autoimmune disease severity.
Human trials using regulatory T cells to treat graft-versus-host disease have shown efficacy.
T regulatory cell transferred to a patient may change into T helper 17 (Th17) cells, which are pro-inflammatory rather than regulatory cells.
Foxp3 is the major transcription factor controlling T-regulatory cells (Treg or CD4+ cells).
CD4+ cells are leukocytes responsible for protecting 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 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 specific transcriptional factors are acting on it.
The Foxp3 gene is also known to convert naïve T-cells to Treg cells.
Foxp3 is capable of regulating the expression of suppression-mediating molecules.
Alterations in numbers of regulatory T cells, particular those that express Foxp3 are found in a number of disease states.
Some tumors have a local relative excess of Foxp3 positive T cells which inhibits the body’s ability to suppress the formation of cancerous cells.
In an autoimmune disease such as systemic lupus erythematosus (SLE) there is a relative dysfunction of Foxp3 positive cells.
The Foxp3 gene is also mutated in IPEX syndrome, with many patients with IPEX having mutations in the DNA-binding forkhead domain of FOXP3.
FoxP3 plays an important role in cancer development.
FoxP3 expression down-regulation has been reported in tumor specimens derived from breast, prostate, and ovarian cancer patients, indicating that FoxP3 is a potential tumor suppressor gene.
Expression of FoxP3 is detected in tumor specimens derived from additional cancer types, including pancreatic, melanoma, liver, bladder, thyroid, cervical cancers.
FoxP3 serves as tumor suppressive transcription factor in cancer development: FoxP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumor suppressor genes P21 and LATS2 in breast and prostate cancer cells.
Over-expression of FoxP3 in melanoma, glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo.
Foxp3 is a recruiter of other anti-tumor enzymes: CD39 and CD8.
The overexpression of CD39 is found in patients with multiple cancer types such as melanoma, leukemia, pancreatic cancer, colon cancer, and ovarian cancer.
This overexpression of CD39 may be protecting tumor cells, allowing them to create their escape phase where the tumor grows quickly and it becomes clinically invisible by becoming independent of the extracellular matrix and creating its own immunosuppressive tumor microenvironment.
The escape phase allows tumors cells to completely evade the immune system, which reduces the immunogenicity and ability to become clinically detected, allowing it to progress and spread throughout the body.
Some cancers have high numbers of mutated CD4+ cells that produce large quantities of TGF-β and IL-10, which suppress signals to the immune system and allow for tumor escape.
Foxp3 polymorphism (rs3761548) May contribute to cancer development like gastric cancer through influencing Treg cell activity and secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β.
Mutations or disruptions of the Foxp3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus.
Foxp3 mutations affect thymocytes developing within the thymus.
Regulated by Foxp3, thymocytes are transformed into mature Treg cells by the thymus.
Patients who have systemic lupus erythematosus (SLE) possess Foxp3 mutations that affect the thymopoiesis process, preventing the proper development of Treg cells within the thymus.
Such malfunctioning Treg cells aren’t efficiently being regulated by its transcription factors, which cause them to attack cells that are healthy, leading to these organ-specific autoimmune diseases.
Foxp3 facilitates the translocation of extracellular adenosine into the cytoplasm 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.