FOXP3

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Forkhead box P3
Identifiers
Symbol(s)	FOXP3; AIID; DIETER; IPEX; JM2; MGC141961; MGC141963; PIDX; XPID
External IDs	OMIM: 300292 MGI: 1891436 Homologene: 8516
Gene ontology Molecular Function: • transcription factor activity • protein binding • zinc ion binding • general transcriptional repressor activity • protein homodimerization activity • sequence-specific DNA binding • metal ion binding • NF-kappaB binding • NFAT protein binding Cellular Component: • intracellular • nucleus • protein complex Biological Process: • negative regulation of T cell cytokine production • chromatin remodeling • transcription • negative regulation of cell proliferation • inhibition of NF-kappaB transcription factor • negative regulation of interferon-gamma production • negative regulation of interleukin-10 production • negative regulation of interleukin-2 production • negative regulation of interleukin-4 production • inhibition of CREB transcription factor • T cell activation • T cell homeostasis • negative regulation of interleukin-2 biosynthetic process • negative regulation of transcription, DNA-dependent • positive regulation of transcription • negative regulation of activated T cell proliferation • negative regulation of cytokine secretion • negative regulation of immune response
RNA expression pattern
Image:PBB GE FOXP3 221333 at tn.png Image:PBB GE FOXP3 221334 s at tn.png More reference expression data
Orthologs
	Human	Mouse
Entrez	50943	20371
Ensembl	ENSG00000049768	ENSMUSG00000039521
Uniprot	Q9BZS1	Q53Z59
Refseq	NM_014009 (mRNA) NP_054728 (protein)	NM_054039 (mRNA) NP_473380 (protein)
Location	Chr X: 48.99 - 49.01 Mb	Chr X: 6.74 - 6.75 Mb
Pubmed search	[1]	[2]

Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators and functions as the master regulator in the development and function of regulatory T cells.

Gene Structure

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 chromosome Xp11.23.

Physiology and pathophysiology

Foxp3 gene is mutated in the X-linked syndrome of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) ^[1]

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 IL2 production, although thymic development appears normal. Histologic analysis indicates that peripheral lymphoid organs, particularly lymph nodes lack cells.

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. ^[1][1][1]

In human disease, alterations in numbers of regulatory T cells, and in particular those that express Foxp3, are found in a number of conditions. For example, patients with tumours have a local relative excess of Foxp3 positive T cells which inhibits the body's ability to suppress the formation of cancerous cells.^[1]

On the other hand, patients with autoimmune disease such as systemic lupus erythematosus have a relative dysfunction of Foxp3 positive cells.^[1]

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.^[1]

These discoveries give hope that cellular therapies using foxp3 positive cells may, one day, help overcome these diseases.

See also

• AIRE
• Anergy
• Autoimmune regulator
• Autoimmunity
• Cell therapy
• Central tolerance
• Cluster of differentiation
• FOX proteins
• Immune system
• Immune tolerance
• Immunity
• Immunology
• Lymphocytes
• T cells
• Thymocyte

References

Further reading

External links

• Immune Tolerance Network
• MeSH FOXP3+protein,+human

v • d • e Transcription factors and intracellular receptors
(1) Basic domains	(1.1) Basic leucine zipper (bZIP) Activating transcription factor (1, 2, 3, 4, 5, 6) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3) • GABPA • MAF (B, F, G, K) • NRL • NRF1 • XBP1 (1.2) Basic helix-loop-helix (bHLH) ATOH1 • AhR • AHRR • ARNT • ASCL1 • BMAL (ARNTL, ARNTL2) • CLOCK • HIF (1A, 3A) • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • NEUROD1 • Twist • USF1 (1.3) bHLH-ZIP Myc • MITF • SREBP (1, 2) (1.6) Basic helix-span-helix (bHSH) AP-2
(2) Zinc finger DNA-binding domains	(2.1) Nuclear receptor (Cys4) subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP) (2.2) Other Cys4 GATA (1, 2, 3, 4, 5, 6) (2.3) Cys2His2 General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH: 1, 2) • GLI-Krüppel family (1, 2, 3, YY1) • KLF (2, 4, 5, 6, 10, 11, 12, 13) • Sp1 • zinc finger (3, 35, 43, 146, 148, 165, 217, 268, 281, 350) • Zbtb7 (7A) • ZBT (16, 17, 33) (2.4) Cys6 HIVEP1
(3) Helix-turn-helix domains	(3.1) Homeo domain ARX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C6, C8, C9, C13, D1, D3, D4, D9, D10, D11, D12, D13) • NANOG • NKX (2-1, 2-5, 3-1) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7) (3.2) Paired box PAX (1, 2, 3, 4, 5, 6, 7, 8, 9) (3.3) Fork head / winged helix E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, L2, M1, N3, O3, O4, P1, P2, P3) (3.4) Heat Shock Factors HSF1 (3.5) Tryptophan clusters ELF (4, 5) • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB (3.6) TEA domain transcriptional enhancer factor 1, 2
(4) β-Scaffold factors with minor groove contacts	(4.1) Rel homology region NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (5, C1, C2, C3, C4) (4.2) STAT STAT (1, 2, 3, 4, 5, 6) (4.3) p53 p53 (4.4) MADS box Mef2 (A, B, C, D) • SRF (4.7) High mobility group HNF (1A, 1B) • LEF1 • SOX (3, 4, 6, 9, 10, 13, 18) • SRY • SSRP1 (4.10) Cold-shock domain CSDA
(0) Other transcription factors	(0.2) HMGI(Y) HMGA (1, 2) (0.3) Pocket domain Rb • RBL1 • RBL2 (0.6) Miscellaneous ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • Rho/Sigma • R-SMAD