STAT4-mediated transcriptional repression of the IL5 gene in human memory Th2 cells

摘要

Type I interferon (IFN-alpha/beta) plays a critical role in suppressing viral replication by driving the transcription of hundreds of interferon-sensitive genes (ISGs). While many ISGs are transcriptionally activated by the ISGF3 complex, the significance of other signaling intermediates in IFN-alpha/beta-mediated gene regulation remains elusive, particularly in rare cases of gene silencing. In human Th2 cells, IFN-alpha/beta signaling suppressed IL5 and IL13 mRNA expression during recall responses to T-cell receptor (TCR) activation. This suppression occurred through a rapid reduction in the rate of nascent transcription, independent of de novo expression of ISGs. Further, IFN-alpha/beta-mediated STAT4 activation was required for repressing the human IL5 gene, and disrupting STAT4 dimerization reversed this effect. This is the first demonstration of STAT4 acting as a transcriptional repressor in response to IFN-alpha/beta signaling and highlights the unique activity of this cytokine to acutely block the expression of an inflammatory cytokine in human T cells.