Helios induces epigenetic silencing of Il2 gene expression in regulatory T cells

摘要

Regulatory T cells play a critical role in maintaining immune tolerance and preventing autoimmune disease. Treg cells express the transcription factor Foxp3, which acts as a master regulator of their differentiation and controls their capacity to suppress T cell responses. Treg cells have an intrinsically anergic phenotype and do not produce IL-2 or proliferate upon stimulation ex vivo. Recent reports have identified that Helios, a member of the Ikaros family of transcription factors, is expressed in Treg cells. However, its specific function is not yet fully understood. In this study, we show that Helios regulates IL-2 production in Treg cells by suppressing the Il2 gene transcription. Loss of Helios in Treg cells breaks their anergic phenotype and results in de-repression of the Il2 locus, allowing Treg cells 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 Treg cells 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 Treg cells also causes a decrease in suppressive capacity. Our results identify Helios as a key regulator of Il2 expression in Treg cells, contributing to the maintenance of the anergic phenotype.