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

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.