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，先天免疫细胞感知外来分子，并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-a/b）是一类促炎细胞因子，在病毒感染期间由先天树突状细胞分泌。IFN-a/b在推动人类CD4+ T细胞分泌高水平IFN-g促进病毒感染细胞的根除方面很重要。然而，在小鼠中，IFN-a/b不促进诱导CD4+ T细胞分泌IFN-g，因为小鼠IFN-a/b受体不激活促进IFN-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，不能反映CD4+ 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-a/b受体的物种特异性成分，该成分促进了人类CD4+ T细胞中STAT4的激活。因此，本项目的目标是：1)通过基因操作重建小鼠T细胞中IFN-a/b依赖性STAT4信号通路；2)确定该通路在转基因小鼠体内干扰素应答中所起的作用。

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.