FOXP3: Wikis

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Forkhead box P3
Identifiers
Symbols FOXP3; AIID; DIETER; IPEX; JM2; MGC141961; MGC141963; PIDX; XPID
External IDs OMIM300292 MGI1891436 HomoloGene8516 GeneCards: FOXP3 Gene
RNA expression pattern
PBB GE FOXP3 221333 at tn.png
PBB GE FOXP3 221334 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 50943 20371
Ensembl ENSG00000049768 ENSMUSG00000039521
UniProt Q9BZS1 Q53Z59
RefSeq (mRNA) NM_014009 NM_054039
RefSeq (protein) NP_054728 NP_473380
Location (UCSC) Chr X:
48.99 - 49.01 Mb
Chr X:
6.74 - 6.75 Mb
PubMed search [1] [2]

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.[1]

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.

Contents

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).[2][3]

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 has recently led to an explosion of research in the biological properties of regulatory T cells (Tregs).[4][5][6] 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.[7] 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 (a Harvard study).

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.[8] Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells.[9] The Foxp3 gene is also mutated in the X-linked IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked).[10] 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.[11] 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

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): 590–7. doi:10.1002/jcp.21001. PMID 17311282.  
  2. ^ 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): 461–8. doi:10.1086/302761. PMID 10677306.  
  3. ^ 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.  
  4. ^ Hori S, Nomura T, Sakaguchi S (2003). "Control of regulatory T cell development by the transcription factor Foxp3". Science 299 (5609): 1057–61. doi:10.1126/science.1079490. PMID 12522256.  
  5. ^ Fontenot JD, Gavin MA, Rudensky AY (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.  
  6. ^ Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (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.  
  7. ^ Suri-Payer E, Fritzsching B (2006). "Regulatory T cells in experimental autoimmune disease". Springer Semin Immunopathol 28 (1): 3–16. doi:10.1007/s00281-006-0021-8. PMID 16838180.  
  8. ^ Beyer M, Schultze J (2006). "Regulatory T cells in cancer". Blood 108 (3): 804–11. doi:10.1182/blood-2006-02-002774. PMID 16861339.  
  9. ^ Alvarado-Sánchez B, Hernández-Castro B, Portales-Pérez D, Baranda L, Layseca-Espinosa E, Abud-Mendoza C, Cubillas-Tejeda A, González-Amaro R (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.  
  10. ^ Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L, Kelly T, Saulsbury F, Chance P, Ochs H (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.  
  11. ^ Brunkow M, Jeffery E, Hjerrild K, Paeper B, Clark L, Yasayko S, Wilkinson J, Galas D, Ziegler S, Ramsdell F (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.  

Further reading

  • 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): 356–61. 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): 21–3. 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): 590–7. 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): 227–35; 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". Adv. Exp. Med. Biol. 601: 27–36. PMID 17712989.  
  • Long E, Wood KJ (2007). "Understanding FOXP3: progress towards achieving transplantation tolerance". Transplantation 84 (4): 459–61. 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): 461–8. doi:10.1086/302761. PMID 10677306.  
  • Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMID 11076863.  
  • 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): R75–81. doi:10.1172/JCI11679. PMID 11120765.  
  • 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): 20–1. 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): 37672–9. 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): 874–6. doi:10.1136/jmg.38.12.874. PMID 11768393.  
  • 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): 127–30. doi:10.1046/j.1365-2249.2002.01940.x. PMID 12296863.  
  • 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): 16899–903. doi:10.1073/pnas.242603899. PMID 12477932.  
  • 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): 149–56. 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): 1437–43. doi:10.1172/JCI200319441. PMID 14597769.  
  • 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): 6034–9. doi:10.1210/jc.2003-031080. PMID 14671208.  

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