Type I Interferon Mediates Th2 Reprogramming and Acute Suppression of Effector Functions
The type I interferon (IFN-α/β) family is a pleiotropic set of cytokines that play a role in regulating many biological functions, including suppressing viral replication and modulating adaptive immune functions. Although IFN-α/β has been extensively studied regarding the activation of interferon sensitive genes, much less is known regarding its role as a negative regulator. Here, I demonstrate a role for IFN-α/β in the regulation of Th2 development as well as memory Th2 cell function. The Th2 master transcription factor GATA3, promotes its own expression through a positive regulatory loop, uncoupling the cell from the requirement of IL-4 signaling. IFN-α/β inhibits this process by inducing epigenetic modifications within the GATA3 locus that prevent this positive regulatory loop from being established. Reduced DNase hypersensitivity and enhanced H3K27me3 correlates with a reduction in GATA3 gene expression by targeting the IL-4-sensitive alternative transcript exon 1a for suppression. These results demonstrate that IFN-α/β interferes with IL-4-mediated programming and induction of GATA3 through the enhancement of gene-silencing histone modifications within the GATA locus. In addition to mediating chromatin modifications required for the long-term suppression of genes, IFN-α/β signaling also acutely suppresses gene expression in pre-committed Th2 cells. Here, I demonstrate the cellular and molecular pathways involved in suppressing the TCR-mediated expression of the human IL5 gene. IFN-α treatment potently suppressed IL5 and IL13 gene expression by reducing the rate of nascent transcription, independent of de novo expression of ISGs. Further, I show that IFN-α-mediated STAT4 activation is required to suppress gene expression. Furthermore, IFN-α/β-mediated acute suppression occurs in a species-specific manner, since murine Th2 cells are not regulated by IFN-α/β signaling in contrast to human Th2 cells. This robust suppression of acute IL5 and IL13 expression, paired with the suppression of Th2 development, provide further evidence that IFN-α/β is a candidate for the treatment of allergic disease.
DNA Methylation, GATA3 Transcription Factor, Interferon-alpha, Signal Transduction, Th2 Cells, Transcription, Genetic
University of Texas Southwestern Medical Center
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