MAP3K8-mediated regulation of adaptive immune responses and autoimmunity

描述（由申请人提供）：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， 自身反应性T细胞识别受影响组织中的自身抗原并分泌破坏性促炎细胞因子。因此，初始T细胞分化成促炎性与致耐受性T辅助细胞谱系调节宿主的免疫状态。T细胞受体（TCR）信号，沿着局部细胞因子，是启动T辅助细胞分化所必需的，并且改变TCR信号强度影响效应子谱系定型。理解有助于TCR信号强度和T辅助细胞分化的精确分子机制在考虑T细胞介导的疾病，特别是自身免疫的免疫疗法时是重要的。我们最近证明了Map 3 k8在幼稚T细胞中转导TCR信号，并有助于指定Th 1转录程序。目前尚不清楚Map 3 k8是如何影响多种TCR信号通路来调节其他T辅助细胞谱系的发育和功能的。该提案的目标是确定丝氨酸-苏氨酸激酶Map 3 k8如何影响TCR信号传导，T辅助细胞分化，并有助于自身免疫。我们的中心假设是，Map 3 k8作为变阻器调节TCR信号的强度，从而改变体内T细胞的谱系定型和效应子功能。Aim 1将研究Map 3 k8如何影响T辅助细胞分化使用体外T细胞极化测定。目的1旨在确定哪些TCR信号通路在Map 3 k8-/-小鼠中存在缺陷，以及它们如何通过基因表达测定、蛋白质印迹、转录因子易位和用慢病毒表达特异性信号分子拯救表型来促进T辅助细胞分化。Aim 2将使用动物模型和药理学抑制剂来确定Map 3 k8如何有助于T细胞介导的自身免疫，并将解决Map 3 k8在人类细胞的T辅助细胞分化中是否具有相似的功能。关于Map 3 k8在TCR信号网络中的作用的知识不仅有助于我们对正常T细胞发育和功能的基本理解，而且还将提供对自身免疫性疾病发病机制的深入了解，最终可能引发治疗和预防的创新方法。

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.