Regulatory T Cells-Related Genes Are under DNA Methylation Influence

Abstract

Regulatory T cells (Tregs) exert a highly suppressive function in the immune system. Disturbances in their function predispose an individual to autoimmune dysregulation, with a predominance of the pro-inflammatory environment. Besides Foxp3, which is a master regulator of these cells, other genes (e.g., Il2ra, Ctla4, Tnfrsf18, Ikzf2, and Ikzf4) are also involved in Tregs development and function. Multidimensional Tregs suppression is determined by factors that are believed to be crucial in the action of Tregs-related genes. Among them, epigenetic changes, such as DNA methylation, tend to be widely studied over the past few years. DNA methylation acts as a repressive mark, leading to diminished gene expression. Given the role of increased CpG methylation upon Tregs imprinting and functional stability, alterations in the methylation pattern can cause an imbalance in the immune response. Due to the fact that epigenetic changes can be reversible, so-called epigenetic modifiers are broadly used in order to improve Tregs performance. In this review, we place emphasis on the role of DNA methylation of the genes that are key regulators of Tregs function. We also discuss disease settings that have an impact on the methylation status of Tregs and systematize the usefulness of epigenetic drugs as factors able to influence Tregs functions.

Updates of cancer hallmarks in patients with inborn errors of immunity

“…As a transcriptional repressor in lymphocytes, Helios, encoded by IKZF2, has a significant role in regulating effector T-cell activity, similar to the previous function described for IKZF1 [103,104].…”

“…As a transcriptional repressor in lymphocytes, Helios, encoded by IKZF2 , has a significant role in regulating effector T-cell activity, similar to the previous function described for IKZF1 [103,104]. Patients with IKZF2 deficiency present with chronic overactivation of proinflammatory cytokine production with this being the most likely driver of tumor predisposition [103] [mainly because of the up-regulation in both interferon-gamma (IFN-γ) and interleukin-2 (IL-2) downstream signaling pathways] [103].…”

Epigenetic Alterations in Inborn Errors of Immunity

“…In the thymus, DNMT1 interaction with FOXP3 (Forkhead Box P3) transcription factor induces Tregs development. Tregs are a heterogeneous population of CD4-positive T cells characterized by a high expression of CD25 and a low expression of CD127 [ 30 ]. After T cell activation, active DNA demethylation is essential for interleukin-2 (IL2) synthesis and for lineage polarization into T helper-1 (Th1), Th2, and Th17 [ 31 , 32 ].…”

DNA Methylation in Regulatory T Cell Differentiation and Function: Challenges and Opportunities

“…Profound DNA hypomethylation at TSDRs was observed in differentiated Treg cells compared with Tconv cells long before the discovery of TET-dependent active demethylation [ 26 , 28 ]. Accumulating evidence now suggests that active DNA demethylation plays a critical role in maintaining Treg cell fate and suppressive function [ 26 , 35 , 56 , 110 , 111 ]. At the Foxp3 locus, enhancers CNS1 and CNS2 are fully demethylated upon Treg lineage commitment.…”