Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases

Abstract

The FOXP3 gene encodes a transcription factor thought to be important for the development and function of regulatory T cells (Treg cells). These cells are involved in the regulation of T cell activation and therefore are essential for normal immune homeostasis. Signals from microenvironment have a profound influence on the maintenance or progression of diseases. Thus, Tregs have an important marker protein, FOXP3, though it does not necessarily confer a Treg phenotype when expressed. FOXP3 polymorphisms that occur with high frequency in the general populations have been studied in common multifactorial human diseases. Dysfunction of FOXP3 gene product could result in lack of Treg cells and subsequently chronically activated CD4+ T cells which express increased levels of several activation markers and cytokines, resulting in some autoimmune diseases. In contrast, high Treg levels have been reported in peripheral blood, lymph nodes, and tumour specimens from patients with different types of cancer. The present study discusses the polymorphisms located in intron, exon and promoter regions of FOXP3 which have already been investigated by many researchers. FOXP3 has received considerable attention in attempts to understand the molecular aspect of Treg cells. Therefore, in the present study, the relationship between genetic polymorphism of FOXP3 in Treg-cell role and in disease development are reviewed considering the interactive effect of genetic factors.

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

“…In humans, polymorphysms of both FoxP3 and PD-1 associate with autoimmunity. Although the mutations that affect the exon of FoxP3 results in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) by itself, others mutations affecting intronic or noncoding regions that might alter the expression levels are relatively mild (6,37). The lessons from our mice show that even such mild SNPs, if both molecules are affected, can provoke severe autoimmunity.…”

“…CTLA-4 also plays a critical role in Treg function. Indeed, deficiency of CTLA-4 or FoxP3 in humans causes lethal autoimmunity (5,6). In mice, genetic ablation of CTLA-4 causes a lympho-proliferative disease that phenocopies FoxP3 deficiency.…”

Association of T-Bet, GATA-3, RORC, and FOXP3 Copy Number Variations With Acute Anterior Uveitis With or Without Ankylosing Spondylitis in Chinese Han

“…The so-called ''T-box'' expressed in T cells (T-bet), GATA binding protein 3 (GATA)-3, retinoid-related orphan receptor ct (RORct) and transcription factor forkhead box protein 3 (FOXP3) are examples of transcription factors that are specific for Th1, Th2, Th17, and T Reg cells, respectively. 8,9 Expression of T-bet is upregulated in uveitis patients with Behçet disease (BD) and Vogt Koyanagi Harada (VKH) syndrome and its expression was shown to parallel inflammation during experimental endotoxin uveitis in rats. [10][11][12] Expression of GATA- 3 has not yet been studied in clinical uveitis, but was shown to be increased during experimental autoimmune uveitis in mice.…”

Association between FOXP3, FOXE1 Gene Polymorphisms and Risk of Differentiated Thyroid Cancer in Chinese Han Population

“…Expression of FOXP3 is crucial for Tregs which may influence its function in several different mechanisms [14]. A number of studies have been performed to investigate the polymorphisms of Foxp3 promoter (rs3761548 and rs2280883) in various diseases including breast cancer in different populations [15]. However, there are no reports of Chinese DTC patients for these three SNPs.…”