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

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.

Keywords: Anergy; CNS2 methylation; Foxp3; Peripheral tolerance; Treg differentiation.

Figure 1.. Anergy induction and anergy-derived Foxp3 ⁺ Treg cell differentiation in a two-step model.

( A) Anergy induction creates Treg cell progenitors with a partially demethylated nTreg-Me signature as a consequence of balanced DNMT1/DNMT3b methyltransferase and TET dioxygenase activities. ( B, C) Anergy reversal is associated with changes in metabolism that control DNA methylation. Dominant DNMT1 function during chromosomal replication ( B) generates daughter cells with fully methylated Foxp3 CNS2 CpG islands that differentiate into Foxp3 ^– effector T cells, whereas dominant TET activity promotes fully demethylated daughter cells ( C) that differentiate into Foxp3 ⁺ Treg cells. α-KG, alpha-ketoglutarate; CNS, conserved non-coding sequence; DNMT, DNA methyltransferase; SAM-e, S-adenosyl methionine; TET, ten-eleven translocation; Treg, regulatory T.

Figure 2.. Varying DNMT1 and TET protein activities during cell cycle progression control the differentiation state of CD4 T cells.

( A) Conventional CD4 T effector (Teff) cell differentiation occurs in highly proliferative cells with unopposed DNMT1 activity maintaining a fully methylated Foxp3 CNS2 region. ( B) Anergy-derived Foxp3 ⁺ Treg cell differentiation is a two-step process. At the end of step 1, anergic T cells undergo partial demethylation at the CNS2 locus as a result of TET dioxygenase activity. Those anergic cells that accumulate the highest number of CNS2 CpG demethylation events become resistant to DNMT1 activity during anergy reversal. In step 2, such anergic Treg cell progenitors fully demethylate their natural Treg demethylation (nTreg-Me) signature genes during chromosomal replication to promote their differentiation to the Foxp3 ⁺ Treg cell lineage. CNS, conserved non-coding sequence; DNMT, DNA methyltransferase; TET, ten-eleven translocation; Treg, regulatory T.