FOXP3

Forkhead box P3
Identifiers
Symbols	FOXP3; AIID; DIETER; IPEX; MGC141961; MGC141963; PIDX; XPID
External IDs	OMIM: 300292 MGI: 1891436 HomoloGene: 8516 GeneCards: FOXP3 Gene
Gene Ontology Molecular function • chromatin binding • double-stranded DNA binding • sequence-specific DNA binding transcription factor activity • sequence-specific DNA binding transcription factor activity • sequence-specific enhancer binding RNA polymerase II transcription factor activity • transcription corepressor activity • protein binding • zinc ion binding • DNA bending activity • histone acetyltransferase binding • protein homodimerization activity • histone deacetylase binding • sequence-specific DNA binding • metal ion binding • protein heterodimerization activity • NF-kappaB binding • NFAT protein binding Cellular component • intracellular • nucleus • nucleus • transcription factor complex • cytoplasm • cytoplasm • protein complex Biological process • negative regulation of transcription from RNA polymerase II promoter • B cell homeostasis • cytokine production • positive regulation of mesenchymal cell proliferation • myeloid cell homeostasis • T cell mediated immunity • tolerance induction to self antigen • regulation of immunoglobulin production • positive regulation of T cell anergy • negative regulation of chronic inflammatory response • negative regulation of T cell cytokine production • positive regulation of peripheral T cell tolerance induction • chromatin remodeling • transcription, DNA-dependent • transcription, DNA-dependent • regulation of transcription, DNA-dependent • pattern specification process • skeletal muscle tissue development • negative regulation of cell proliferation • response to virus • embryo development • post-embryonic development • cerebellum development • caudate nucleus development • putamen development • cerebral cortex development • negative regulation of histone deacetylation • negative regulation of NF-kappaB transcription factor activity • negative regulation of interferon-gamma production • negative regulation of interleukin-10 production • negative regulation of interleukin-2 production • negative regulation of interleukin-4 production • negative regulation of interleukin-5 production • negative regulation of interleukin-6 production • negative regulation of tumor necrosis factor production • negative regulation of CREB transcription factor activity • positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation • positive regulation of transforming growth factor-beta1 production • positive regulation of immature T cell proliferation in thymus • positive regulation of histone acetylation • negative regulation of histone acetylation • growth • negative regulation of cytokine biosynthetic process • T cell activation • negative regulation of T cell proliferation • vocal learning • camera-type eye development • T cell homeostasis • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of interferon-gamma biosynthetic process • negative regulation of interleukin-2 biosynthetic process • negative regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • negative regulation of activated T cell proliferation • lung alveolus development • negative regulation of isotype switching to IgE isotypes • regulation of isotype switching to IgG isotypes • smooth muscle tissue development • negative regulation of cytokine secretion • negative regulation of immune response • T cell receptor signaling pathway • righting reflex • positive regulation of epithelial cell proliferation involved in lung morphogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	50943	20371
Ensembl	ENSG00000049768	ENSMUSG00000039521
UniProt	Q9BZS1	Q53Z59
RefSeq (mRNA)	NM_001114377.1	NM_054039
RefSeq (protein)	NP_001107849.1	NP_473380
Location (UCSC)	Chr X: 49.11 – 49.12 Mb	Chr X: 7.16 – 7.17 Mb
PubMed search	[1]	[2]

FOXP3 (forkhead box P3) is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator in the development and function of regulatory T cells.

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, Xp11.23).

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 (a/iTregs) T cells gave a molecular anchor to the population of regulatory T cells (Tregs), previously identified by non-specific markers such as CD25 or CD45RB. In animal studies, Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-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 (autoimmune) disease severity in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease. These discoveries give hope that cellular therapies using Foxp3 positive cells may, one day, help overcome these diseases. Unfortunately recent T cell biology investigations revealed that T cell nature is much more plastic than initially thought. Thus the regulatory T cell therapy may in fact be very risky as the T regulatory cell transferred to the patient may reverse and become another proinflammatory T cell.(see recent papers from Romagnani, Stockinger etc.). Th17 (T helper 17) cells are proinflammatory and are produced under very 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 and as such 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). It seems so far that murine studies point to IL-6 whereas human studies have shown IL-21 (Citation needed).

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. 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 the X-linked IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked). 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. 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

Further reading

• Wu Y, Borde M, Heissmeyer V et al. (2006). "FOXP3 controls regulatory T cell function through cooperation with NFAT". Cell 126 (2): 375–387. doi:10.1016/j.cell.2006.05.042. PMID 16873067. 
• Schmidt-Weber CB, Blaser K (2006). "The role of the FOXP3 transcription factor in the immune regulation of allergic asthma". Current allergy and asthma reports 5 (5): 356–361. doi:10.1007/s11882-005-0006-z. PMID 16091206. 
• Li B, Samanta A, Song X et al. (2006). "FOXP3 ensembles in T-cell regulation". Immunol. Rev. 212: 99–113. doi:10.1111/j.0105-2896.2006.00405.x. PMID 16903909. 
• Ziegler SF (2007). "FOXP3: not just for regulatory T cells anymore". Eur. J. Immunol. 37 (1): 21–23. doi:10.1002/eji.200636929. PMID 17183612. 
• Zhang L, Zhao Y (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. 
• Bacchetta R, Gambineri E, Roncarolo MG (2007). "Role of regulatory T cells and FOXP3 in human diseases". J. Allergy Clin. Immunol. 120 (2): 227–235. doi:10.1016/j.jaci.2007.06.023. PMID 17666212. 
• Ochs HD, Torgerson TR (2007). "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance: model for autoaggression". Adv. Exp. Med. Biol.. Advances in Experimental Medicine and Biology 601: 27–36. doi:10.1007/978-0-387-72005-0_3. ISBN 978-0-387-72004-3. PMID 17712989. 
• Long E, Wood KJ (2007). "Understanding FOXP3: progress towards achieving transplantation tolerance". Transplantation 84 (4): 459–461. doi:10.1097/01.tp.0000275424.52998.ad. PMID 17713426. 
• Bennett CL, Yoshioka R, Kiyosawa H et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1288099. 
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=310948. 
• Chatila TA, Blaeser F, Ho N et al. (2001). "JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome". J. Clin. Invest. 106 (12): R75–R81. doi:10.1172/JCI11679. PMC 387260. PMID 11120765. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=387260. 
• Wildin RS, Ramsdell F, Peake J et al. (2001). "X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy". Nat. Genet. 27 (1): 18–20. doi:10.1038/83707. PMID 11137992. 
• Bennett CL, Christie J, Ramsdell F et al. (2001). "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3". Nat. Genet. 27 (1): 20–21. doi:10.1038/83713. PMID 11137993. 
• Brunkow ME, Jeffery EW, Hjerrild KA et al. (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. 
• Schubert LA, Jeffery E, Zhang Y et al. (2001). "Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation". J. Biol. Chem. 276 (40): 37672–37679. doi:10.1074/jbc.M104521200. PMID 11483607. 
• Kobayashi I, Shiari R, Yamada M et al. (2002). "Novel mutations of FOXP3 in two Japanese patients with immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX)". J. Med. Genet. 38 (12): 874–876. doi:10.1136/jmg.38.12.874. PMC 1734795. PMID 11768393. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1734795. 
• Tommasini A, Ferrari S, Moratto D et al. (2002). "X-chromosome inactivation analysis in a female carrier of FOXP3 mutation". Clin. Exp. Immunol. 130 (1): 127–130. doi:10.1046/j.1365-2249.2002.01940.x. PMC 1906506. PMID 12296863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1906506. 
• Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Bassuny WM, Ihara K, Sasaki Y et al. (2003). "A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes". Immunogenetics 55 (3): 149–156. doi:10.1007/s00251-003-0559-8. PMID 12750858. 
• Walker MR, Kasprowicz DJ, Gersuk VH et al. (2003). "Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells". J. Clin. Invest. 112 (9): 1437–1443. doi:10.1172/JCI200319441. PMC 228469. PMID 14597769. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=228469. 
• Owen CJ, Jennings CE, Imrie H et al. (2004). "Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome". J. Clin. Endocrinol. Metab. 88 (12): 6034–6039. doi:10.1210/jc.2003-031080. PMID 14671208. 

External links

• GeneReviews/NIH/NCBI/UW entry on IPEX Syndrome
• MeSH FOXP3+protein,+human