FOXP3

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)

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.

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.

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.

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

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.

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