FOXP3 is a master regulator of immune homeostasis expressed specifically in CD4⁺ CD25⁺ T regulatory cells controlling their growth, development and function.  FOXP3 significance in the normal development of Tregs is better elucidated with the fact that mutated FOXP3 results in a rare and fatal early onset autoimmune disorder in humans called XLAAD/IPEX (human immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), a condition phenotypically similar to Scurfy in mice. 

FOXP3 is primarily an oligomeric, transcriptional repressor protein that belongs to the P subfamily of forkhead (FKH)-winged helix family of transcriptional factors. Members of this subfamily are forkhead (FKH) box proteins characterized by the presence of a highly conserved C-terminal winged-helix/FKH DNA binding domain (DBD) and centrally-located C2H2 zinc finger domain and leucine zipper domain.  Apart from these, an additional N-terminal proline rich region is present in FOXP3, whose function is yet to be understood. Studies have shown that FOXP3 is a nuclear-localized protein that specifically trans-represses NF-AT-induced expression of cytokines and other transcriptional factors in Tregs including IL-2, IL-4, IFN-gamma and NF-κB.

However, FOXP3 is not the sole master switch regulating the origin and development of CD4⁺ CD25⁺ Tregs. Studies have confirmed the existence of splice variant forms FOXP3 that are specifically expressed in humans but are lacking in mouse. Cloning and RT-PCR analysis from mRNA of CD4⁺ CD25⁺ T regulatory cells (Allan et. al, Smith et. al) has shown that these cells express two different alternatively spliced variant forms of FOXP3. While the FOXP3Δ2 variant had a deleted 105bp exon2 region, there was another FOXP3Δ2, Δ7 variant that had an additional 81bp exon7 deletion apart from exon2 deletion. The predicted molecular weight of this FOXP3Δ2 is ~4KDa lower than the molecular weight of FOXP3.  Transient transfection assays using Jurkat cells suggest that the FOXP3Δ2 is novel splice variant that functions as a transcriptional repressor protein and acts in cohort with FOXP3 causing a significant suppression of cytokines and up-regulating the expression of various Treg-associated markers.

The existence of the splice variant forms of FOXP3 protein suggests an additional level of complexity related to the biology of FOXP3.  A lot research needs to be done so as to elucidate the physiological and functional importance of FOXP3 splice variant forms towards maintaining immune homeostasis in Tregs and preventing autoimmune disorders.