Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. (138.20)

Abstract

Abstract CD4+ regulatory T cells (Tregs) maintain immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses. The core genetic program of Tregs and their ability to suppress pathologic immune responses depends on the transcription factor Foxp3. Despite progress in understanding mechanisms of Foxp3-dependent gene activation, the molecular mechanism of Foxp3-dependent gene repression remains largely unknown. Here we identify Eos, a zinc-finger transcription factor of the Ikaros family, as a critical mediator of Foxp3-dependent gene silencing in Tregs. By qRT-PCR analysis we found that Eos is highly expressed in the CD4+CD25+ and CD4+Foxp3+ population of T cells. Additionally, Eos interacts directly with Foxp3 and induces chromatin modifications that result in gene silencing in Tregs. Silencing of Eos in Tregs abrogates their ability to suppress naïve T cell proliferation in vitro. Furthermore, Tregs with Eos knockdown fail to protect recipient Rag2-/- mice from severe colitis when co-transferred with naïve (CD4+CD25- CD62Lhigh ) T cells. Eos silencing in Tregs also endows these cells with partial effector function. These results demonstrate the critical role that Eos plays in Treg programming. They also raise the possibility that the interaction between Foxp3 and Eos may be a therapeutic target for controlling pathological immune responses in which excessive Treg activity plays an important role such as cancer and chronic infections.