95 : Type I interferon regulates acute IL-5 and IL-13 expression in human memory CD4+ T cells

Abstract

Type I Interferon (IFN- α / β ) is a critical anti-viral cytokine and is currently being used to treat Hepatitis C viral infections and multiple sclerosis, among other diseases. Although the positive regulatory effects of this cytokine have been studied, less is known about its role as a negative regulator of gene expression. Previously, we demonstrated that IFN- α / β suppresses Th2 development in human naive CD4+ T cells by negatively regulating GATA3 expression, leading to the suppression of IL-4, IL-5 and IL-13. Based on this data, we were interested in how IFN- α / β might affect other T cell types. In the current study, we interrogated the effects of IFN- α / β on human memory CD4+ T cells. We hypothesized that IFN- α / β has similar negative regulatory effects on memory CD4+ T cells, leading to decreased Th2 cytokine expression. Human memory CD4+ T cells were acutely stimulated in the presence of IFN- α . Interestingly, IL-5 and IL-13 gene expression was suppressed, however, IL-4 expression was unaffected. Further, IFN- α / β signaling, but not IFN- γ or IFN- λ , suppressed IL-5 and IL-13 expression. Nuclear run-on studies demonstrated that IFN- α / β signaling suppressed de novo transcription of IL-5 and IL-13, and this suppression did not require the translation of interferon-sensitive genes. Our data indicate that this negative regulatory pathway acted upstream of gene expression, and suggested that IFN- α / β was able to acutely suppress specific gene expression. Currently, we are assessing direct STAT2 binding by ChIP-Seq, which will identify potential cis-regulatory regions necessary for IL-5 and L-13 gene modulation. Together, these results suggest that IFN- α / β could have many benefits in suppressing multiple aspects of Th2 development and effector function in atopic asthma.