Search

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. [ABSTRACT FROM AUTHOR]

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 naïve 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. [ABSTRACT FROM AUTHOR]