Species-specific IFN-a/b-dependent Th1 development

描述(申请人提供)：在原发病毒感染期间，先天免疫细胞感知外来分子，进而通过分泌促炎细胞因子来警示手臂效应淋巴细胞。I型干扰素(IFN-a/b)是一类在病毒感染过程中由固有树突状细胞分泌的促炎细胞因子。干扰素-a/b在推动人类CD4+T细胞的发育中发挥重要作用，以分泌高水平的干扰素-g，从而促进病毒感染细胞的根除。然而，在小鼠中，干扰素-a/b并不促进CD4+T细胞分泌干扰素-g，因为小鼠干扰素-a/b受体不会激活促进干扰素-g分泌所需的关键下游转录因子STAT4。这一重要途径在小鼠体内被阻断，并没有反映出CD4+T细胞在人类感染病毒过程中所起的重要作用。我们的实验室已经发现了人类干扰素-a/b受体的物种特异性成分，它可以促进人类CD4+T细胞中STAT4的激活。因此，该项目的目标是1)通过基因操作在小鼠T细胞中重建依赖于干扰素a/b的STAT4信号，以及2)确定该途径在转基因小鼠体内干扰素反应中所起的作用。

DESCRIPTION (provided by applicant): During primary virus infections, innate immune cells sense foreign molecules and, in turn alert and arm effector lymphocytes by secreting pro-inflammatory cytokines. Type I interferons (IFN-a/b) are a class of pro-inflammatory cytokines that are secreted by innate dendritic cells during virus infections. IFN-a/b is important in driving the development of human CD4+ T cells to secrete high levels of IFN-g that promotes the eradication of virally-infected cells. However, in mice, IFN-a/b does not promote the induction of IFN-g secretion from CD4+ T cells because the murine IFN-a/b receptor does not activate the critical down-stream transcription factor, STAT4, required to promote IFN-g secretion. This important pathway is blocked in mice and does not reflect the important role that CD4+ T cells play during virus infections in humans. Our lab has discovered the species-specific component for the human IFN-a/b receptor that promotes STAT4 activation in human CD4+ T cells. Therefore, the goals of this project are 1) To reconstitute IFN-a/b-dependent STAT4 signaling in murine T cells by genetic manipulation, and 2) Determine the role that this pathway plays during in vivo interferon responses in genetically altered mice.