Abstract
Abstract Ikaros (encoded by Ikzf1) is a lymphocyte-specific transcription factor that controls a wide spectrum of T cell functions, including T helper differentiation, cytokine production, and tolerance in response to antigenic stimuli. Using heterozygous and dominant-negative mouse models, we have shown previously that Ikaros controls IL-2 production by conventional T cells, T helper differentiation, CD8+ effector differentiation, and anergy induction. While the role of Ikaros in many T cell subsets has been established, its role in Treg-mediated peripheral tolerance has not been examined. To examine the Treg-specific role of Ikaros, we generated Ikzf1-fl/fl-Foxp3-YFP-Cre+ mouse with conditional deletion of Ikaros in Tregs. Ikzf1-fl/fl-Foxp3-YFP-Cre+ mouse exhibited enlarged secondary lymphoid tissues, with increased frequencies of effector memory Tconv and Treg. We show that Ikaros expression by Tregs is required for immune tolerance in an allogenic cardiac transplant model. While CD28- and CD40L-blockade induced long-term cardiac allograft tolerance in control recipients, Ikzf1-fl/fl-Foxp3-YFP-Cre+ recipients rejected the allografts in a short duration (p<0.01). We show that Ikaros forms a complex with Foxp3, which is required for Foxp3 to bind to and repress inflammatory cytokine genes. Ikaros is also required for normal iTreg development in vitro, as TGF-B/IL-2-induced iTreg development is impaired in conventional CD4+ T cells with reduced Ikaros activity. These studies suggest that Ikaros interacts with Foxp3 and directs Foxp3 to exert its suppressive function in Tregs.
Published Version
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