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

描述（由申请人提供）：在原发性病毒感染期间，先天性免疫细胞感知外来分子，进而通过分泌促炎细胞因子来警告和武装效应淋巴细胞。I型干扰素（IFN-α/B）是一类在病毒感染期间由先天性树突状细胞分泌的促炎细胞因子。IFN-a/B在驱动人CD 4 + T细胞的发育以分泌促进病毒感染细胞的根除的高水平IFN-g方面是重要的。然而，在小鼠中，IFN-α/B不促进IFN-γ从CD 4 + T细胞分泌的诱导，因为鼠IFN-α/B受体不激活促进IFN-γ分泌所需的关键下游转录因子STAT 4。这一重要途径在小鼠中被阻断，并不反映CD 4 + T细胞在人类病毒感染过程中发挥的重要作用。我们的实验室已经发现了人类IFN-α/B受体的物种特异性组分，其促进人类CD 4 + T细胞中的STAT 4活化。因此，本项目的目标是1）通过遗传操作重建小鼠T细胞中IFN-α/b依赖性STAT 4信号传导，以及2）确定该途径在遗传改变的小鼠体内干扰素应答期间所起的作用。

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.