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

I型干扰素（IFN）的诱导是初次接触侵入性细菌和病毒的主要反应。在人类中，I型ifn包括一个由12个IFNa亚型组成的家族，这些亚型具有显著的蛋白质序列相似性。它们还具有显著的功能同源性，并通过相同的干扰素α受体（IFNAR）发出信号，诱导多种干扰素刺激基因（ISGs）的表达，这些基因编码抗病毒蛋白和免疫反应的调节因子。我们对IFNa反应的大部分了解都假设不同的IFNa亚型在功能上是冗余的。最近的进展表明，IFNa亚型在功能上是不同的，可以导致不同感染的不同结果。尽管人们越来越认识到不同IFNa亚型的可变生物活性，但对于IFNa亚型如何通过差异调节免疫反应来介导不同的结果，人们知之甚少。我的研究计划的长期目标是了解每一种不同的IFNa亚型如何对免疫反应的调节做出贡献。在本研究中，我们将使用人原代细胞和细胞系来研究不同人IFNa亚型的免疫调节作用。我们将重点关注免疫的三个主要组成部分，我们以前观察到不同亚型之间的差异效应。短期目标是：1)我们已经检测到IFNa亚型对细胞毒性细胞（如细胞毒性T淋巴细胞和自然杀伤细胞）的不同影响。我们将研究特定IFNa亚型调节这些关键细胞毒性细胞亚群的效应功能的能力。2)我们已经确定了单个IFNa亚型诱导树突状细胞（DC）成熟的能力差异。我们将评估单个IFNa亚型对DC成熟和抗原呈递的影响，以及它们启动CD8和CD4 T细胞的能力。3)我们已经确定了内在抗病毒因子，这些因子在响应特定的IFNa亚型时差异表达或激活。我们将比较由特定IFNa亚型诱导的因子的抗病毒活性，并研究驱动差异的分子机制。这些研究将有助于更好地理解IFNa亚型对免疫系统适应性、先天和内在臂的不同影响；一个长期未被探索的基础免疫学领域。更好地了解IFNa亚型如何调节免疫功能，可以更好地了解特定IFNa亚型在微调免疫反应以介导不同感染的不同结果中的作用。

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.