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一起是启动T细胞分化所必需的，改变TCR信号强度会影响效应者的谱系承诺。当考虑T细胞介导的疾病的免疫治疗时，了解TCR信号强度和辅助性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、T辅助细胞分化以及对自身免疫的贡献。我们的中心假设是，Map3k8作为变阻器调节TCR信号的强度，从而改变体内T细胞的谱系承诺和效应器功能。AIM1将使用体外T细胞极化分析来研究Map3k8如何影响辅助性T细胞分化。目的1通过基因表达分析、Western blotting、转录因子易位和慢病毒表达特定信号分子的表型挽救，探讨哪些TCR信号通路在Map3k8-/-小鼠体内存在缺陷，以及它们对辅助性T细胞分化的影响。AIM2将利用动物模型和药物抑制剂确定Map3k8如何促进T细胞介导的自身免疫，并将解决Map3k8在人类细胞的T辅助细胞分化中是否起到类似的作用。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, and altering the TCR signal strength influences effector lineage commitment. Understanding the precise molecular mechanisms contributing to TCR signal strength 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 contributes to autoimmunity. Our central hypothesis is that Map3k8 acts as a rheostat to modulate the strength of TCR signals and thereby alters lineage commitment and effector functions of T cells in vivo. Aim1 will examine how Map3k8 influences T helper cell differentiation using in vitro T cell polarization assays. Aim 1 seeks to determine which TCR signaling pathways are defective in Map3k8-/- mice and how they contribute to T helper cell differentiation using gene expression assays, Western blotting, transcription factor translocation and rescue of the phenotype with lentiviral expression of specific signaling molecules. Aim2 will determine how Map3k8 contributes to T cell-mediated autoimmunity using both animal models and pharmacologic inhibitors and will address whether Map3k8 functions similarly in T helper differentiation of human 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.