FOXP3

FOXP3 (forkhead box P3) is a gene involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as the master regulator in the development and function of regulatory T cells.cite journal | author = Zhang L, Zhao Y | title = The regulation of Foxp3 expression in regulatory CD4(+)CD25(+)T cells: multiple pathways on the road | journal = J. Cell. Physiol. | volume = 211 | issue = 3 | pages = 590–7 | year = 2007 | month = June | pmid = 17311282 | doi = 10.1002/jcp.21001 | url = | issn = ]

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.

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, X"p"11.23).cite journal | author = Bennett CL, Yoshioka R, Kiyosawa H, Barker DF, Fain PR, Shigeoka AO, Chance PF | title = X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3 | journal = Am. J. Hum. Genet. | volume = 66 | issue = 2 | pages = 461–8 | year = 2000 | month = February | pmid = 10677306 | pmc = 1288099 | doi = 10.1086/302761 | url = | issn = ] cite journal | author = Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F | title = Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse | journal = Nat. Genet. | volume = 27 | issue = 1 | pages = 68–73 | year = 2001 | month = January | pmid = 11138001 | doi = 10.1038/83784 | url = | issn = ]

Physiology

The discovery of Foxp3 as a specific marker of regulatory T cells has recently led to an explosion of research in the biological properties of regulatory T cells. [cite journal |author=Hori S, Nomura T, Sakaguchi S |title=Control of regulatory T cell development by the transcription factor Foxp3 |journal=Science |volume=299 |issue=5609 |pages=1057–61 |year=2003 |pmid=12522256 |doi=10.1126/science.1079490] [cite journal |author= Fontenot JD, Gavin MA, Rudensky AY |title= Foxp3 programs the development and function of CD4+CD25+ regulatory T cells |journal=Nature Immunology |volume=4 |issue=4 |pages=330–6 |year=2003 |pmid=12612578 |doi= 10.1038/ni904] [cite journal |author= Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY |title= Regulatory T cell lineage specification by the forkhead transcription factor Foxp3 |journal=Immunity |volume=22 |issue=3 |pages=329–41 |year=2005 |pmid= 15780990 |doi= 10.1016/j.immuni.2005.01.016] In animal studies, regulatory T cells that express Foxp3 are critical in the transfer of immune tolerance, so that hopefully in the future this knowledge can be used to prevent transplant graft rejection. The induction or administration of Foxp3 positive T cells has, in animal studies, led to marked reductions in disease severity in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease. [cite journal |author=Suri-Payer E, Fritzsching B |title=Regulatory T cells in experimental autoimmune disease |journal=Springer Semin Immunopathol |volume=28 |issue=1 |pages=3–16 |year=2006 |pmid=16838180 |doi=10.1007/s00281-006-0021-8] These discoveries give hope that cellular therapies using Foxp3 positive cells may, one day, help overcome these diseases.

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. [cite journal |author=Beyer M, Schultze J |title=Regulatory T cells in cancer |journal=Blood |volume=108 |issue=3 |pages=804–11 |year=2006 |pmid=16861339 |doi=10.1182/blood-2006-02-002774] Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells. [cite journal |author=Alvarado-Sánchez B, Hernández-Castro B, Portales-Pérez D, Baranda L, Layseca-Espinosa E, Abud-Mendoza C, Cubillas-Tejeda A, González-Amaro R |title=Regulatory T cells in patients with systemic lupus erythematosus |journal=J Autoimmun |volume=27 |issue=2 |pages=110–8 |year=2006 |pmid=16890406 |doi=10.1016/j.jaut.2006.06.005] The Foxp3 gene is also mutated in the X-linked "IPEX" syndrome ("I"mmunodysregulation, "P"olyendocrinopathy, and "E"nteropathy, "X"-linked). [cite journal |author=Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L, Kelly T, Saulsbury F, Chance P, Ochs H |title=The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 |journal=Nat Genet |volume=27 |issue=1 |pages=20–1 |year=2001 |pmid=11137993 |doi=10.1038/83713] 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. [cite journal |author=Brunkow M, Jeffery E, Hjerrild K, Paeper B, Clark L, Yasayko S, Wilkinson J, Galas D, Ziegler S, Ramsdell F |title=Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse |journal=Nat Genet |volume=27 |issue=1 |pages=68–73 |year=2001 |pmid=11138001 |doi=10.1038/83784] 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.

See also

* Autoimmune regulator (AIRE)
* Autoimmunity
* Central tolerance
* Immunity
* Lymphocytes
* Thymocyte

References

Further reading

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