Иммундық жүйедегі FOXP3 ақуызының ролі

Immune response protein

FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. 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. 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. 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.

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).

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. 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. Human trials using regulatory T cells to treat graft versus host disease have shown efficacy. Further work has shown that T cells are more plastic in nature than originally thought. 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. CD4+ cells are leukocytes responsible for protecting animals from foreign invaders such as bacteria and viruses. 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. Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells. The Foxp3 gene is also mutated in IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X linked). Many patients with IPEX have mutations in the DNA binding forkhead domain of FOXP3. 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. 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. 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. 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. 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.