Helios Induces Epigenetic Silencing of Il2 Gene Expression in Regulatory T Cells

Regulatory T cells (Tregs) play a critical role in maintaining immune tolerance and preventing autoimmune disease. Tregs express the transcription factor Foxp3, which acts as a master regulator of their differentiation and controls their capacity to suppress T cell responses. Tregs have an intrinsically anergic phenotype and do not produce IL-2 or proliferate upon stimulation ex vivo. Recent studies identified that Helios, a member of the Ikaros family of transcription factors, is expressed in Tregs. However, its specific function is not fully understood. In this study, we show that Helios regulates IL-2 production in Tregs by suppressing Il2 gene transcription. Loss of Helios in Tregs breaks their anergic phenotype and results in derepression of the Il2 locus, allowing Tregs to display increased baseline proliferation and to produce IL-2 following stimulation. Conversely, forced expression of Helios in CD4(+)Foxp3(-) T cells results in a loss of their normal ability to produce IL-2. Helios acts by binding to the Il2 promoter and inducing epigenetic modifications that include histone deacetylation. We also show that loss of Helios in Tregs results in decreased Foxp3 binding to the Il2 promoter, indicating that Helios promotes binding of Foxp3 to the Il2 promoter. Interestingly, the loss of Helios in Tregs also causes a decrease in suppressive capacity. Our results identify Helios as a key regulator of Il2 expression in Tregs, contributing to the maintenance of the anergic phenotype. The Journal of Immunology, 2013, 190: 1008-1016.