Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation

Abstract

The discovery of the transcription factor Forkhead box-p3 (Foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of T regulatory (Treg) cells, a cell population with a key immunoregulatory role. Work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of Foxp3 in Treg cells. The equilibrium between phenotypic plasticity and stability of Treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate Foxp3 expression. Recent reports have suggested that specific modifications of DNA and histones are required for the establishment of the chromatin structure in conventional CD4 + T (Tconv) cells for their future differentiation into the Treg cell lineage. In this review, we discuss the molecular events that control Foxp3 gene expression and address the associated alterations observed in human diseases. Also, we explore how Foxp3 influences the gene expression programs in Treg cells and how unique properties of Treg cell subsets are defined by other transcription factors.

Intrauterine IPEX

“…Subsequently, many studies on the role of miRNAs in Treg differentiation and stability were conducted, mostly using murine models. These studies revealed a more complex picture, with a least 20 miRNAs exerting important effects on Treg development, control of FOXP3 stability and translation, and suppression of Treg function, such as miRNA-155, regulated by FOXP3 and involved in Treg proliferation, and miR-428, a hominidspecific miRNA, that potently and specifically up-regulate FOXP3 expression accelerating the differentiation of human naïve cells to induced Tregs (30)(31)(32). Additionally, it should be recalled that FOXP3 interacts with several RNA-binding proteins, thus playing a role in the posttranscriptional mechanisms involved in RNA stability (33).…”

Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii

“…Foxp3 transcription is induced in Tregs by T cell receptor (TCR) signaling. Upon its expression, an autoregulatory transcriptional circuit stabilizes Foxp3 gene expression to consolidate Treg differentiation and activate the suppressive function [ 36 ]. The block of Foxp3 elicits Treg depletion and it promotes enhanced stimulation of effector immune mechanisms [ 37 ].…”

The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer

“…FOXP3 is a transcription factor that regulates the function of CD4 Treg cells. The molecular mechanisms regulating FOXP3 are complex and consist of finely tuned transcriptional and epigenetic events [ 56 ]. Although the role of BRD4 and inhibition of FOXP3 were previously unknown, our data suggest that BRDs can regulate the expression of FOXP3.…”