Anergy into T regulatory cells: an integration of metabolic cues and epigenetic changes at the Foxp3 conserved non-coding sequence 2.

Milagros Silva Morales,Daniel Mueller

doi:10.12688/f1000research.16551.1

Abstract

Peripheral immune self-tolerance relies on protective mechanisms to control autoreactive T cells that escape deletion in the thymus. Suppression of autoreactive lymphocytes is necessary to avoid autoimmunity and immune cell–mediated damage of healthy tissues. An intriguing relationship has emerged between two mechanisms of peripheral tolerance—induction of anergy and Foxp3 + regulatory T (Treg) cells—and is not yet well understood. A subpopulation of autoreactive anergic CD4 T cells is a precursor of Treg cells. We now hypothesize that phenotypic and mechanistic features of Treg cells can provide insights to understand the mechanisms behind anergy-derived Treg cell differentiation. In this short review, we will highlight several inherent similarities between the anergic state in conventional CD4 T cells as compared with fully differentiated natural Foxp3 + Treg cells and then propose a model whereby modulations in metabolic programming lead to changes in DNA methylation at the Foxp3 locus to allow Foxp3 expression following the reversal of anergy.

Highlights

Foxp3+ regulatory T (Treg) cells and the induction of anergy in conventional CD4 T cells each represent peripheral tolerance mechanisms designed to control autoreactive CD4 T cells that escape negative selection in the thymus[1]
DNMT1 can once again be inhibited by reduced S-adenosyl methionine (SAM-e) levels as well as increased competition for CNS2 methylcytosine binding by active α-KG/ten-eleven translocation (TET) dioxygenase complexes
In particular, may be important to the differentiation of anergy-derived Treg cells: (a) oxidative phosphorylation (OXPHOS) metabolism and the avoidance of mechanistic target of rapamycin (mTOR)-dependent nutrient uptake promote the accumulation of α-KG/TETdependent hydroxymethylation events within the Foxp[3] CNS2 cis-acting element of resting cells. (b) mTOR-dependent proliferation and chromosomal replication subsequently allow for the demethylation of all daughter-strand CNS2 CpG nucleotides as a consequence of the antagonism between DNMT1 and TET proteins, when the locus is already partially demethylated

Summary

Introduction

Foxp3+ regulatory T (Treg) cells and the induction of anergy in conventional CD4 T cells each represent peripheral tolerance mechanisms designed to control autoreactive CD4 T cells that escape negative selection in the thymus[1]. We understand that exFoxp[3] cells can regain their capacity to express the Foxp[3] gene and suppress CD4 T-cell responses following proliferation in the presence of IL246,50 This predicts a role for CD25-triggered activation of mTOR-dependent glutaminolysis and aerobic glycolysis and the resultant upregulation of α-KG/TET-mediated antagonism of DNMT1 function during chromosomal replication. We hypothesize that high DNMT1 and SAM-e levels, chromosomal replication, and Foxp[3] CNS2 remethylation promote the differentiation of dangerous conventional CD4 Teff cells following the reversal of anergy This is true when an anergic T cell has accumulated only a modest number of hydroxymethylated and demethylated CpG nucleotides at the Figure 1. DNMT1 can once again be inhibited by reduced SAM-e levels as well as increased competition for CNS2 methylcytosine binding by active α-KG/TET dioxygenase complexes

Conclusions

Findings

Mueller DL