Jonathan P. Huber

Regulation of effector and memory T-cell functions by type I interferon.

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.

Cutting Edge: Type I IFN Reverses Human Th2 Commitment and Stability by Suppressing GATA3

T helper 2 cells regulate inflammatory responses to helminth infections while also mediating pathological processes of asthma and allergy. IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor, and the Th2 phenotype is stabilized by a GATA3-dependent autoregulatory loop. In this study, we found that type I IFN (IFN-α/β) blocked human Th2 development and inhibited cytokine secretion from committed Th2 cells. This negative regulatory pathway was operative in human but not mouse CD4+ T cells and was selective to type I IFN, as neither IFN-γ nor IL-12 mediated such inhibition. IFN-α/β blocked Th2 cytokine secretion through the inhibition of GATA3 during Th2 development and in fully committed Th2 cells. Ectopic expression of GATA3 via retrovirus did not overcome IFN-α/β–mediated inhibition of Th2 commitment. Thus, we demonstrate a novel role for IFN-α/β in blocking Th2 cells, suggesting its potential as a promising therapy for atopy and asthma.

IFN-α Suppresses GATA3 Transcription from a Distal Exon and Promotes H3K27 Trimethylation of the CNS-1 Enhancer in Human Th2 Cells

CD4+ 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 IFN (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 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 noncoding sequence (CNS-1) upstream of exon 1A. IFN-α/β treatment led 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.