Summary Type I interferon (IFN‐α/β) is comprised of a family of highly related molecules that exert potent antiviral activity by interfering with virus replication and spread. IFN‐α/β secretion is tightly regulated through pathogen sensing pathways that are operative in most somatic cells. However, specialized antigen‐presenting plasmacytoid dendritic cells are uniquely equipped with the capacity to secrete extremely high levels of IFN‐α/β, suggesting a key role for this cytokine in priming adaptive T‐cell responses. Recent studies in both mice and humans have demonstrated a role for IFN‐α/β in directly influencing the fate of both CD4+ and CD8+ T cells during the initial phases of antigen recognition. As such, IFN‐α/β, among other innate cytokines, is considered an important ‘third signal’ that shapes the effector and memory T‐cell pool. Moreover, IFN‐α/β also serves as a counter‐regulator of T helper type 2 and type 17 responses, which may be important in the treatment of atopy and autoimmunity, and in the development of novel vaccine adjuvants.

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CD4+ T helper type 2 (Th2) development is regulated by the zinc finger transcription factor GATA3. Once induced by acute priming signals, such as IL-4, GATA3 poises the Th2 cytokine locus for rapid activation and establishes a positive feedback loop that maintains elevated GATA3 expression. Type I interferon (IFN-α/β) inhibits Th2 cells by blocking the expression of GATA3 during Th2 development and in fully committed Th2 cells. In this study, we have uncovered a unique mechanism by which IFN-α/β signaling represses the GATA3 gene in human Th2 cells. IFN-α/β suppressed expression of GATA3 mRNA that was transcribed from an alternative distal upstream exon (1A). This suppression was not mediated through DNA methylation, but rather by histone modifications localized to a conserved non-coding sequence (CNS-1) upstream of exon 1A. IFN-α/β treatment lead to a closed conformation of CNS-1 as assessed by DNase I hypersensitivity along with enhanced accumulation of H3K27me3 mark at this CNS region, which correlated with increased density of total nucleosomes at this putative enhancer. Consequently, accessibility of CNS-1 to GATA3 DNA binding activity was reduced in response to IFN-α/β signaling, even in the presence of IL-4. Thus, IFN-α/β disrupts the GATA3 autoactivation loop and promotes epigenetic silencing of a Th2-specific regulatory region within the GATA3 gene.

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