IFNa subtype-specific modulation of intrinsic, innate and adaptive immunity.

点击翻译按钮获取中文摘要

Induction of type I interferon (IFN) is the primary response to initial contact with invasive bacteria and viruses. In humans, type I IFNs comprise a family of 12 IFNa subtypes that share significant protein sequence similarity. They also have significant functional homology and signal through the same interferon alpha receptor (IFNAR) to induce expression of a variety of interferon-stimulated genes (ISGs) that encode anti-viral proteins and moderators of the immune response. Much of what we know about the IFNa response assumes that the different IFNa subtypes are functionally redundant. Recent advances have indicated that IFNa subtypes are functionally distinct and can result in differential outcomes to distinct infections. Despite growing recognition of the variable biological activities of different IFNa subtypes, very little is known about how IFNa subtypes differentially regulate the immune response to mediate distinct outcomes. The long-term objective of my research program is to understand how each of the different IFNa subtypes contribute to modulation of the immune response. In this proposal we will use human primary cells and cell lines to study the immunomodulatory effects of different human IFNa subtypes. We will focus on three main components of immunity where we have previously observed differential effects between subtypes. The short term objectives are to: 1) We have detected differential impacts of IFNa subtypes on cytotoxic cells such as cytotoxic T lymphocytes and natural killer cells. We will investigate the ability of specific IFNa subtypes to modulate the effector functions of these key cytotoxic cell subsets. 2) We have identified differences in the ability of individual IFNa subtypes to induce dendritic cell (DC) maturation. We will evaluate the effects of individual IFNa subtypes on maturation and antigen presentation by DC and on their ability to prime both CD8 and CD4 T cells. 3) We have identified intrinsic antiviral factors that are differentially expressed or activated in response to specific IFNa subtypes. We will compare the antiviral activity of the factors induced by specific IFNa subtypes and investigate the molecular mechanism driving the differences. These studies will lead to a better understanding of the distinct effects IFNa subtypes have on the adaptive, innate and intrinsic arms of the immune system; an area of basic immunology that has long remained unexplored. Greater understanding how IFNa subtypes modulate immune function could lead to better understanding of the role of specific IFNa subtypes in fine-tuning the immune response to mediate differential outcomes to distinct infections.