Transcriptional and Epigenetic Regulation of the Type III IFN Response.

摘要

Cytokines are signaling molecules that play an indispensable role in maintaining homeostasis and relaying intercellular communication in the immune system. Interferons (iFNs) are a subset of cytokines that effectively restrict the replication and dissemination of many microbial pathogens. As the most recently identified member of the classical IFN family, type III IFN (IFN-lambda) exhibits similar antiviral and anti-proliferative activities to type I IFN (IFN-alpha/beta) but also possesses many interesting and unique features.;Resembling IFN-alpha and IFN-beta, upon binding to its cognate receptor complex, IFN-lambda signals through the classical JAK-STAT pathway and induces IFN-stimulated gene (ISG) expression. Despite appearing to be mediated via identical signaling cascades, type I and type III IFNs have divergent biological activities. However, it remains unclear whether or not these functionally related cytokines activate common or distinct patterns of ISGs. It is tempting to speculate that IFN-lambda triggers the expression of a specialized group of ISGs, which would partially account for its non-redundant role in the immune system. It is also possible that IFN-lambda exhibits a distinctive temporal kinetics in activating signal transduction and the downstream events. This varying dynamics in cytokine signaling may prove essential against certain infections in an in vivo context.;Another major disparity between type I and type III IFNs is the utilization of different receptors and how these complexes are spatially regulated. In contrast to the ubiquitous expression of IFN-alpha/beta receptor on virtually all cell types, IFN-lambda receptor, especially the alpha subunit that confers ligand-binding specificity, is confined to the lung, intestine and liver, but not found in immune cells or other parts of the body such as the blood and brain. Despite the consensus that IFN-lambda plays a pivotal role in the antiviral response at mucosal surfaces, the molecular mechanisms that contribute to restricted IFN-lambda receptor expression remain unknown. On the basis of understanding the underlying regulatory network, both antiviral and antitumor functions of IFN-lambda could be harnessed via up-regulation of receptor levels in formerly insensitive cell types.;In this dissertation, I will discuss both the temporal and spatial regulation of the type III IFN response from transcriptional and epigenetic perspectives. This study will expand the current knowledge of IFN-lambda and explore the potential clinical uses of the cytokine by examining its distinctive signaling patterns and the mechanisms regulating its receptor distribution.