FOXP3

Forkhead box P3
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3QRF​, 4WK8​
Identifiers
Symbols	FOXP3 ; AIID; DIETER; IPEX; JM2; PIDX; XPID
External IDs	OMIM: 300292 MGI: 1891436 HomoloGene: 8516 GeneCards: FOXP3 Gene
Gene ontology Molecular function • sequence-specific DNA binding RNA polymerase II transcription factor activity • core promoter binding • sequence-specific DNA binding transcription factor activity • RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity • transcription corepressor activity • protein binding • histone acetyltransferase binding • protein homodimerization activity • histone deacetylase binding • sequence-specific DNA binding • metal ion binding • NF-kappaB binding • NFAT protein binding Cellular component • nucleus • cytoplasm • protein complex Biological process • negative regulation of transcription from RNA polymerase II promoter • B cell homeostasis • cytokine production • myeloid cell homeostasis • CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment • T cell mediated immunity • tolerance induction to self antigen • regulation of T cell anergy • 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 • regulation of transcription, DNA-templated • transcription from RNA polymerase II promoter • negative regulation of cell proliferation • response to virus • anatomical structure morphogenesis • cell differentiation • 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-17 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 • positive regulation of interleukin-4 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 • negative regulation of cytokine biosynthetic process • T cell activation • negative regulation of T cell proliferation • 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-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • negative regulation of activated T cell proliferation • negative regulation of isotype switching to IgE isotypes • regulation of isotype switching to IgG isotypes • negative regulation of cytokine secretion • negative regulation of immune response • T cell receptor signaling pathway • negative regulation of T-helper 17 cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	50943	20371
Ensembl	ENSG00000049768	ENSMUSG00000039521
UniProt	Q9BZS1	Q99JB6
RefSeq (mRNA)	NM_001114377	NM_001199347
RefSeq (protein)	NP_001107849	NP_001186276
Location (UCSC)	Chr X: 49.25 – 49.26 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.^[1] A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells.^[2][3][4] 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.^[5][6]

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.^[7]

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).^[1][8]

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.^[2][3][4] In animal studies, Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-tolerance.^[9]

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.^[10] Human trials using regulatory T cells to treat graft-versus-host disease have shown efficacy.^[11][12]

Further work has shown that T cells are more plastic in nature than originally thought.^[13][14][15] 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.^[13] Th17 cells are proinflammatory and are produced under similar environments as a/iTregs.^[13] 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.^[16] Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells.^[17] The Foxp3 gene is also mutated in the X-linked IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked).^[18] 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.^[1] 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,^[19] 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

• Autoimmune regulator (AIRE)
• Autoimmunity
• Central tolerance
• Immunity
• IPEX syndrome
• Lymphocytes
• Thymocyte

References

1. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (Jan 2001). "Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse". Nature Genetics 27 (1): 68–73. doi:10.1038/83784. PMID 11138001.
2. Hori S, Nomura T, Sakaguchi S (Feb 2003). "Control of regulatory T cell development by the transcription factor Foxp3". Science 299 (5609): 1057–61. doi:10.1126/science.1079490. PMID 12522256.
3. Fontenot JD, Gavin MA, Rudensky AY (Apr 2003). "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells". Nature Immunology 4 (4): 330–6. doi:10.1038/ni904. PMID 12612578.
4. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (Mar 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.
5. Josefowicz SZ, Lu LF, Rudensky AY (January 2012). "Regulatory T cells: mechanisms of differentiation and function". Annual Review of Immunology 30 (January): 531–64. doi:10.1146/annurev.immunol.25.022106.141623. PMID 22224781.
6. Zhang L, Zhao Y (Jun 2007). "The regulation of Foxp3 expression in regulatory CD4(+)CD25(+)T cells: multiple pathways on the road". Journal of Cellular Physiology 211 (3): 590–7. doi:10.1002/jcp.21001. PMID 17311282.
7. Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA (Feb 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.
8. Bennett CL, Yoshioka R, Kiyosawa H, Barker DF, Fain PR, Shigeoka AO, Chance PF (Feb 2000). "X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3". American Journal of Human Genetics 66 (2): 461–8. doi:10.1086/302761. PMC 1288099. PMID 10677306.
9. Ohki H, Martin C, Corbel C, Coltey M, Le Douarin NM (Aug 1987). "Tolerance induced by thymic epithelial grafts in birds". Science 237 (4818): 1032–5. doi:10.1126/science.3616623. PMID 3616623.
10. Suri-Payer E, Fritzsching B (Aug 2006). "Regulatory T cells in experimental autoimmune disease". Springer Seminars in Immunopathology 28 (1): 3–16. doi:10.1007/s00281-006-0021-8. PMID 16838180.
11. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE (Jan 2011). "Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics". Blood 117 (3): 1061–70. doi:10.1182/blood-2010-07-293795. PMID 20952687.
12. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, Del Papa B, Zei T, Ostini RI, Cecchini D, Aloisi T, Perruccio K, Ruggeri L, Balucani C, Pierini A, Sportoletti P, Aristei C, Falini B, Reisner Y, Velardi A, Aversa F, Martelli MF (Apr 2011). "Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation". Blood 117 (14): 3921–8. doi:10.1182/blood-2010-10-311894. PMID 21292771.
13. Zhou L, Chong MM, Littman DR (May 2009). "Plasticity of CD4+ T cell lineage differentiation". Immunity 30 (5): 646–55. doi:10.1016/j.immuni.2009.05.001. PMID 19464987.
14. Bluestone JA, Mackay CR, O'Shea JJ, Stockinger B (Nov 2009). "The functional plasticity of T cell subsets". Nature Reviews. Immunology 9 (11): 811–6. doi:10.1038/nri2654. PMID 19809471.
15. Murphy KM, Stockinger B (Aug 2010). "Effector T cell plasticity: flexibility in the face of changing circumstances". Nature Immunology 11 (8): 674–80. doi:10.1038/ni.1899. PMID 20644573.
16. Beyer M, Schultze JL (Aug 2006). "Regulatory T cells in cancer". Blood 108 (3): 804–11. doi:10.1182/blood-2006-02-002774. PMID 16861339.
17. Alvarado-Sánchez B, Hernández-Castro B, Portales-Pérez D, Baranda L, Layseca-Espinosa E, Abud-Mendoza C, Cubillas-Tejeda AC, González-Amaro R (Sep 2006). "Regulatory T cells in patients with systemic lupus erythematosus". Journal of Autoimmunity 27 (2): 110–8. doi:10.1016/j.jaut.2006.06.005. PMID 16890406.
18. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (Jan 2001). "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3". Nature Genetics 27 (1): 20–1. doi:10.1038/83713. PMID 11137993.
19. 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 (Jan 2014). "FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis". Oncotarget 5 (1): 264–76. doi:10.18632/oncotarget.1600. PMC 3960207. PMID 24406338.

Further reading

• Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, Mathis D, Benoist C, Chen L, Rao A (Jul 2006). "FOXP3 controls regulatory T cell function through cooperation with NFAT". Cell 126 (2): 375–87. doi:10.1016/j.cell.2006.05.042. PMID 16873067.
• Schmidt-Weber CB, Blaser K (Sep 2005). "The role of the FOXP3 transcription factor in the immune regulation of allergic asthma". Current Allergy and Asthma Reports 5 (5): 356–61. doi:10.1007/s11882-005-0006-z. PMID 16091206.
• Li B, Samanta A, Song X, Furuuchi K, Iacono KT, Kennedy S, Katsumata M, Saouaf SJ, Greene MI (Aug 2006). "FOXP3 ensembles in T-cell regulation". Immunological Reviews 212: 99–113. doi:10.1111/j.0105-2896.2006.00405.x. PMID 16903909.
• Ziegler SF (Jan 2007). "FOXP3: not just for regulatory T cells anymore". European Journal of Immunology 37 (1): 21–3. doi:10.1002/eji.200636929. PMID 17183612.
• Bacchetta R, Gambineri E, Roncarolo MG (Aug 2007). "Role of regulatory T cells and FOXP3 in human diseases". The Journal of Allergy and Clinical Immunology 120 (2): 227–35; quiz 236–7. 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". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology 601: 27–36. doi:10.1007/978-0-387-72005-0_3. PMID 17712989.
• Long E, Wood KJ (Aug 2007). "Understanding FOXP3: progress towards achieving transplantation tolerance". Transplantation 84 (4): 459–61. doi:10.1097/01.tp.0000275424.52998.ad. PMID 17713426.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM (Dec 2000). "JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome". The Journal of Clinical Investigation 106 (12): R75–81. doi:10.1172/JCI11679. PMC 387260. PMID 11120765.
• Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (Jan 2001). "X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy". Nature Genetics 27 (1): 18–20. doi:10.1038/83707. PMID 11137992.
• Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF (Oct 2001). "Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation". The Journal of Biological Chemistry 276 (40): 37672–9. doi:10.1074/jbc.M104521200. PMID 11483607.
• Kobayashi I, Shiari R, Yamada M, Kawamura N, Okano M, Yara A, Iguchi A, Ishikawa N, Ariga T, Sakiyama Y, Ochs HD, Kobayashi K (Dec 2001). "Novel mutations of FOXP3 in two Japanese patients with immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX)". Journal of Medical Genetics 38 (12): 874–6. doi:10.1136/jmg.38.12.874. PMC 1734795. PMID 11768393.
• Tommasini A, Ferrari S, Moratto D, Badolato R, Boniotto M, Pirulli D, Notarangelo LD, Andolina M (Oct 2002). "X-chromosome inactivation analysis in a female carrier of FOXP3 mutation". Clinical and Experimental Immunology 130 (1): 127–30. doi:10.1046/j.1365-2249.2002.01940.x. PMC 1906506. PMID 12296863.
• Bassuny WM, Ihara K, Sasaki Y, Kuromaru R, Kohno H, Matsuura N, Hara T (Jun 2003). "A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes". Immunogenetics 55 (3): 149–56. doi:10.1007/s00251-003-0559-8. PMID 12750858.
• Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, Ziegler SF (Nov 2003). "Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells". The Journal of Clinical Investigation 112 (9): 1437–43. doi:10.1172/JCI19441. PMC 228469. PMID 14597769.
• Owen CJ, Jennings CE, Imrie H, Lachaux A, Bridges NA, Cheetham TD, Pearce SH (Dec 2003). "Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome". The Journal of Clinical Endocrinology and Metabolism 88 (12): 6034–9. doi:10.1210/jc.2003-031080. PMID 14671208.

External links

• GeneReviews/NIH/NCBI/UW entry on IPEX Syndrome
• FOXP3 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)