FOXP3

Forkhead box P3
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsFOXP3 ; AIID; DIETER; IPEX; PIDX; XPID
External IDsOMIM: 300292 MGI: 1891436 HomoloGene: 8516 GeneCards: FOXP3 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez5094320371
EnsemblENSG00000049768ENSMUSG00000039521
UniProtQ9BZS1Q99JB6
RefSeq (mRNA)NM_001114377NM_001199347
RefSeq (protein)NP_001107849NP_001186276
Location (UCSC)Chr HG1436_HG1432_PATCH:
49.11 – 49.12 Mb		Chr X:
7.58 – 7.6 Mb
PubMed search

FOXP3 (forkhead box P3) also known as scurfin is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator (transcription factor) in the development and function of regulatory T cells.[1] Regulatory T cells generally turn the immune response down. In cancer, 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 can allow other autoimmune cells to attack the body's own tissues.

While the precise control mechanism has not yet been established, FOX proteins belong to the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription. In regulatory T cell model systems, the FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, and may repress transcription of key genes following stimulation of T cell receptors.[2]

Structure

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).[3][4]

Physiology

The discovery of Foxp3 as a specific marker of natural T regulatory cells (nTregs, a lineage of T cells) and adaptive/induced T regulatory cells (a/iTregs) gave a molecular anchor to the population of regulatory T cells (Tregs), previously identified by non-specific markers such as CD25 or CD45RB.[5][6][7]

In animal studies, 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 in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease.[8] Human trials have produced weaker results.

Unfortunately, recent T cell biology investigations revealed that T cell nature is more plastic than initially thought. Thus regulatory T cell therapy may be risky, as the T regulatory cell transferred to the patient may reverse and become another proinflammatory T cell[9][10]. T helper 17 (Th17) cells are proinflammatory and are produced under similar environments as a/iTregs. Th17 cells are produced under the influence of TGF-β and IL-6 (or IL-21), whereas a/iTregs are produced under the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. Murine studies point to IL-6 whereas human studies have shown IL-21.

Pathophysiology

In human disease, alterations in numbers of regulatory T cells – and in particular those that express Foxp3 – are 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.[11] Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells.[12] The Foxp3 gene is also mutated in the X-linked IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked).[13] These mutations were in the forkhead domain of FOXP3, indicating that the mutations may disrupt critical DNA interactions.

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.[4] 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 was 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 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,[14] 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.

See also

References

  1. ↑ Zhang L, Zhao Y (June 2007). "The regulation of Foxp3 expression in regulatory CD4(+)CD25(+)T cells: multiple pathways on the road". J. Cell. Physiol. 211 (3): 590–597. doi:10.1002/jcp.21001. PMID 17311282.
  2. ↑ Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA (February 2007). "Foxp3 occupancy and regulation of key target genes during T-cell stimulation". Nature 445 (7130): 931–5. doi:10.1038/nature05478. PMC 3008159. PMID 17237765.
  3. ↑ Bennett CL, Yoshioka R, Kiyosawa H, Barker DF, Fain PR, Shigeoka AO, Chance PF (February 2000). "X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3". Am. J. Hum. Genet. 66 (2): 461–468. doi:10.1086/302761. PMC 1288099. PMID 10677306.
  4. ↑ 4.0 4.1 Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (January 2001). "Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse". Nat. Genet. 27 (1): 68–73. doi:10.1038/83784. PMID 11138001.
  5. ↑ Hori S, Nomura T, Sakaguchi S (February 2003). "Control of regulatory T cell development by the transcription factor Foxp3". Science 299 (5609): 1057–61. doi:10.1126/science.1079490. PMID 12522256.
  6. ↑ Fontenot JD, Gavin MA, Rudensky AY (April 2003). "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells". Nat. Immunol. 4 (4): 330–6. doi:10.1038/ni904. PMID 12612578.
  7. ↑ Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (March 2005). "Regulatory T cell lineage specification by the forkhead transcription factor foxp3". Immunity 22 (3): 329–41. doi:10.1016/j.immuni.2005.01.016. PMID 15780990.
  8. ↑ Suri-Payer E, Fritzsching B (August 2006). "Regulatory T cells in experimental autoimmune disease". Springer Semin. Immunopathol. 28 (1): 3–16. doi:10.1007/s00281-006-0021-8. PMID 16838180.
  9. ↑ Romagnani
  10. ↑ Stockinger
  11. ↑ Beyer M, Schultze JL (August 2006). "Regulatory T cells in cancer". Blood 108 (3): 804–11. doi:10.1182/blood-2006-02-002774. PMID 16861339.
  12. ↑ Alvarado-Sánchez B, Hernández-Castro B, Portales-Pérez D, Baranda L, Layseca-Espinosa E, Abud-Mendoza C, Cubillas-Tejeda AC, González-Amaro R (September 2006). "Regulatory T cells in patients with systemic lupus erythematosus". J. Autoimmun. 27 (2): 110–8. doi:10.1016/j.jaut.2006.06.005. PMID 16890406.
  13. ↑ Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (January 2001). "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3". Nat. Genet. 27 (1): 20–1. doi:10.1038/83713. PMID 11137993.
  14. ↑ Tan B, Anaka M, Deb S, Freyer C, Ebert LM, Chueh AC, Al-Obaidi S, Behren A, Jayachandran A, Cebon J, Chen W, Mariadason JM (Dec 20, 2013). "FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis.". Oncotarget 5 (1): 264–76. PMC 3960207. PMID 24406338.

Further reading

External links