Biology:FOXP3

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Short description: Immune response protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 inhibit 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.[citation needed] Foxp3 is the major transcription factor controlling T-regulatory cells (Treg or CD4+ cells).[16] CD4+ cells are leukocytes responsible for protecting animals from foreign invaders such as bacteria and viruses.[16] Defects in this gene's ability to function can cause IPEX syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome as well as numerous cancers.[17] While CD4+ cells are heavily regulated and require multiple transcription factors such as STAT-5 and AhR in order to become active and function properly, Foxp3 has been identified as the master regulator for Treg lineage.[16] Foxp3 can either act as a transcriptional activator or suppressor depending on what specific transcriptional factors such as deacetylases and histone acetylases are acting on it.[16] The Foxp3 gene is also known to convert naïve T-cells to Treg cells, which are capable of an in vivo and in vitro suppressive capabilities suggesting that Foxp3 is capable of regulating the expression of suppression-mediating molecules.[16] Clarifying the gene targets of Foxp3 could be crucial to the comprehension of the suppressive abilities of Treg cells.

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.[18] Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells.[19] The Foxp3 gene is also mutated in IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked).[20][21] Many patients with IPEX have mutations in the DNA-binding forkhead domain of FOXP3.[22]

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.[citation needed]

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.[citation needed]

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,[citation needed] 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.[citation needed]

Foxp3 is a recruiter of other anti-tumor enzymes such as CD39 and CD8.[17] The overexpression of CD39 is found in patients with multiple cancer types such as melanoma, leukemia, pancreatic cancer, colon cancer, and ovarian cancer.[17] This overexpression may be protecting tumorous cells, allowing them to create their “escape phase”.[17] A cancerous tumor's “escape phase” is where the tumor grows quickly and it becomes clinically invisible by becoming independent of the extracellular matrix and creating its own immunosuppressive tumor microenvironment.[17] The consequences of a cancer cell reaching the “escape phase” is that it allows it to completely evade the immune system, which reduces the immunogenicity and ability to become clinically detected, allowing it to progress and spread throughout the body. Some cancer patients have also been known to display higher numbers of mutated CD4+ cells. These mutated cells will then produce large quantities of TGF-β and IL-10, (a Transforming Growth Factor β and an inhibitory cytokine respectively,) which will suppress signals to the immune system and allow for tumor escape.[17] So, Foxp3 polymorphism (rs3761548) might contribute to cancer development like gastric cancer through influencing Treg cell activity and secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β.[23] In one experiment a 15-mer synthetic peptide, P60, was able to inhibit Foxp3's ability to function. P60 did this by entering the cells and then binding to Foxp3, where it hinders Foxp3's ability to translocate to the nucleus.[24] Due to this, Foxp3 could no longer properly suppress the transcription factors NF-kB and NFAT; both of which are protein complexes that regulate transcription of DNA, cytokine production and cell survival.[24] This would inhibit a cell's ability to perform apoptosis and stop its own cell cycle, which could potentially allow an affected cancerous cell to survive and reproduce.

Autoimmune

Mutations or disruptions of the Foxp3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus.[25] These mutations affect thymocytes developing within the thymus. Regulated by Foxp3, it's these thymocytes that during thymopoiesis, are transformed into mature Treg cells by the thymus.[25] It was found that patients who have the autoimmune disease systemic lupus erythematosus (SLE) possess Foxp3 mutations that affect the thymopoiesis process, preventing the proper development of Treg cells within the thymus.[25] These malfunctioning Treg cells aren’t efficiently being regulated by its transcription factors, which cause them to attack cells that are healthy, leading to these organ-specific autoimmune diseases. Another way that Foxp3 helps keep the autoimmune system at homeostasis is through its regulation of the expression of suppression-mediating molecules. For instance, Foxp3 is able to facilitate the translocation of extracellular adenosine into the cytoplasm.[26] It does this by recruiting CD39, a rate-limiting enzyme that's vital in tumor suppression to hydrolyze ATP to ADP in order to regulate immunosuppression on different cell populations.[26]

See also

References

  1. ↑ 1.0 1.1 1.2 "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. January 2001. doi:10.1038/83784. PMID 11138001. 
  2. ↑ 2.0 2.1 "Control of regulatory T cell development by the transcription factor Foxp3". Science 299 (5609): 1057–61. February 2003. doi:10.1126/science.1079490. PMID 12522256. Bibcode: 2003Sci...299.1057H. 
  3. ↑ 3.0 3.1 "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells". Nature Immunology 4 (4): 330–6. April 2003. doi:10.1038/ni904. PMID 12612578. 
  4. ↑ 4.0 4.1 "Regulatory T cell lineage specification by the forkhead transcription factor foxp3". Immunity 22 (3): 329–41. March 2005. doi:10.1016/j.immuni.2005.01.016. PMID 15780990. 
  5. ↑ "Regulatory T cells: mechanisms of differentiation and function". Annual Review of Immunology 30 (January): 531–64. January 2012. doi:10.1146/annurev.immunol.25.022106.141623. PMID 22224781. 
  6. ↑ "The regulation of Foxp3 expression in regulatory CD4(+)CD25(+)T cells: multiple pathways on the road". Journal of Cellular Physiology 211 (3): 590–7. June 2007. doi:10.1002/jcp.21001. PMID 17311282. 
  7. ↑ "Foxp3 occupancy and regulation of key target genes during T-cell stimulation". Nature 445 (7130): 931–5. February 2007. doi:10.1038/nature05478. PMID 17237765. Bibcode: 2007Natur.445..931M. 
  8. ↑ "X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3". American Journal of Human Genetics 66 (2): 461–8. February 2000. doi:10.1086/302761. PMID 10677306. 
  9. ↑ "Tolerance induced by thymic epithelial grafts in birds". Science 237 (4818): 1032–5. August 1987. doi:10.1126/science.3616623. PMID 3616623. Bibcode: 1987Sci...237.1032O. 
  10. ↑ "Regulatory T cells in experimental autoimmune disease". Springer Seminars in Immunopathology 28 (1): 3–16. August 2006. doi:10.1007/s00281-006-0021-8. PMID 16838180. 
  11. ↑ "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. January 2011. doi:10.1182/blood-2010-07-293795. PMID 20952687. 
  12. ↑ "Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation". Blood 117 (14): 3921–8. April 2011. doi:10.1182/blood-2010-10-311894. PMID 21292771. 
  13. ↑ 13.0 13.1 13.2 "Plasticity of CD4+ T cell lineage differentiation". Immunity 30 (5): 646–55. May 2009. doi:10.1016/j.immuni.2009.05.001. PMID 19464987. 
  14. ↑ "The functional plasticity of T cell subsets". Nature Reviews. Immunology 9 (11): 811–6. November 2009. doi:10.1038/nri2654. PMID 19809471. 
  15. ↑ "Effector T cell plasticity: flexibility in the face of changing circumstances". Nature Immunology 11 (8): 674–80. August 2010. doi:10.1038/ni.1899. PMID 20644573. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 "Regulatory T cells and Foxp3" (in en). Immunological Reviews 241 (1): 260–8. May 2011. doi:10.1111/j.1600-065X.2011.01018.x. PMID 21488902. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 "Control of regulatory T cell development by the transcription factor Foxp3" (in en). Science 299 (5609): 1057–61. February 2003. doi:10.1126/science.1079490. PMID 12522256. Bibcode: 2003Sci...299.1057H. 
  18. ↑ "Regulatory T cells in cancer". Blood 108 (3): 804–11. August 2006. doi:10.1182/blood-2006-02-002774. PMID 16861339. 
  19. ↑ "Regulatory T cells in patients with systemic lupus erythematosus". Journal of Autoimmunity 27 (2): 110–8. September 2006. doi:10.1016/j.jaut.2006.06.005. PMID 16890406. 
  20. ↑ "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3". Nature Genetics 27 (1): 20–1. January 2001. doi:10.1038/83713. PMID 11137993. 
  21. ↑ "Regulatory T Cells in Cancer". Annual Review of Cancer Biology 4 (1): 459–477. 2020-03-09. doi:10.1146/annurev-cancerbio-030419-033428. 
  22. ↑ "IPEX as a result of mutations in FOXP3". Clinical & Developmental Immunology 2007: 89017. 2007. doi:10.1155/2007/89017. PMID 18317533. 
  23. ↑ "Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients". Cytokine 138: 155351. February 2021. doi:10.1016/j.cyto.2020.155351. ISSN 1043-4666. PMID 33127257. https://www.sciencedirect.com/science/article/pii/S1043466620303677. 
  24. ↑ 24.0 24.1 "A peptide inhibitor of FOXP3 impairs regulatory T cell activity and improves vaccine efficacy in mice" (in en). Journal of Immunology 185 (9): 5150–9. November 2010. doi:10.4049/jimmunol.1001114. PMID 20870946. 
  25. ↑ 25.0 25.1 25.2 "Control of regulatory T cell development by the transcription factor Foxp3" (in en). Science 299 (5609): 1057–61. February 2003. doi:10.1126/science.1079490. PMID 12522256. Bibcode: 2003Sci...299.1057H. 
  26. ↑ 26.0 26.1 "Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection". Medicine 95 (40): e4989. October 2016. doi:10.1097/md.0000000000004989. PMID 27749555. 

Further reading

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