MAP3K8-mediated regulation of adaptive immune responses and autoimmunity

描述(申请人提供)：自身免疫性疾病正在接近流行水平，估计影响5-8%的美国人口。发病机制在很大程度上归因于 自我反应性T细胞，识别受影响组织中的自身抗原，并分泌破坏性的促炎细胞因子。因此，幼稚T细胞分化为促炎T辅助细胞和耐受T辅助细胞系调节宿主的免疫状态。T细胞受体(TCR)信号和局部细胞因子是启动T细胞分化所必需的。当考虑T细胞介导的疾病的免疫治疗时，了解TCR信号整合和辅助性T细胞分化的确切分子机制是重要的，特别是自身免疫。我们最近证明了Map3k8在初始T细胞中传递TCR信号，并帮助指定Th1转录程序。目前尚不清楚的是，Map3k8是如何影响多个TCR信号通路来调节其他T辅助细胞系的发育和功能的。这项研究的目的是确定丝氨酸-苏氨酸激酶Map3k8如何影响TCR信号、辅助性T细胞分化和自身免疫。我们的中心假设是，Map3k8调节TCR信号整合，从而改变体内T细胞的谱系承诺和效应器功能。AIM1试图通过基因表达分析、Western blotting和转录因子核转位来确定Map3k8-/-T细胞中哪些TCR信号通路是缺陷的。AIM2将研究Map3k8如何影响辅助性T细胞的分化，并将通过体外T细胞极化分析和对切除Map3k8的小鼠T细胞群的分析，探讨特定信号分子和途径在指定辅助性T细胞命运中的作用。AIM3将使用转基因动物模型和Map3k8药物抑制剂来确定Map3k8如何在T细胞介导的自身免疫中发挥作用。实验将通过分析Map3k8-/-T细胞的T细胞迁移、积累和效应器功能来解决疾病(或保护)的潜在机制。对Map3k8在TCR信号网络中作用的了解不仅有助于我们对正常T细胞发育和功能的基本了解，还将有助于深入了解自身免疫性疾病的发病机制，最终可能引发治疗和预防这些疾病的创新方法。

DESCRIPTION (provided by applicant): Autoimmune diseases are approaching epidemic levels, estimated to affect 5-8% of the U.S. population. Pathogenesis is attributed, in large part, to self-reactive T cells that recognize auto-antigens in affected tissues and secrete destructive, pro-inflammatory cytokines. Consequently, the differentiation of naive T cells into pro- inflammatory versus tolerogenic T helper cell lineages regulates the immunologic state of the host. T cell receptor (TCR) signals, along with local cytokines, are required for initiating T helpr cell differentiation. Understanding the precise molecular mechanisms contributing to TCR signal integration and T helper cell differentiation is important when considering immunotherapies for T cell-mediated diseases, particularly autoimmunity. We recently demonstrated that Map3k8 transduces TCR signals in naive T cells and helps to specify a Th1 transcriptional program. What is not clear is precisely how Map3k8 impinges upon the multiple TCR signaling pathways to regulate the development and functions of other T helper cell lineages. The goal of this proposal is to determine how the serine-threonine kinase Map3k8 influences TCR signaling, T helper cell differentiation, and autoimmunity. Our central hypothesis is that Map3k8 modulates TCR signal integration and thereby alters lineage commitment and effector functions of T cells in vivo. Aim1 seeks to determine which TCR signaling pathways are defective in Map3k8-/- T cells using gene expression assays, Western blotting, and transcription factor nuclear translocation. Aim2 will examine how Map3k8 influences T helper cell differentiation and will address the roles of specific signaling molecules and pathways in specifying T helper cell fates using in vitro T cell polarization assays and analysis of T cell populations in mice with Map3k8 ablation. Aim3 will determine how Map3k8 contributes to T cell-mediated autoimmunity using genetically altered animal models and Map3k8 pharmacologic inhibitors. Experiments will address the underlying mechanisms of disease (or protection) by analyzing T cell migration, accumulation, and effector functions of Map3k8-/- T cells. Knowledge gained about the role of Map3k8 in TCR signaling networks will not only contribute to our fundamental understanding of normal T cell development and functions, but will also provide insight into the pathogenesis of autoimmune diseases that may ultimately elicit innovative approaches to their treatment and prevention.