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.[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.
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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]
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.[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 (Citation needed).
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.
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