Transcription Factor T-belt in Dendritic Cells

描述（由申请人提供）：与na的区别T辅助细胞（Th）分化为Th 1和Th 2亚群是通过分泌不同的细胞因子决定对细胞内和/或细胞外病原体的免疫应答的重要过程。转录因子c-Maf和加塔-3指导Th 2谱系定型，而我们实验室最近发现的T-bet作为Th 1细胞分化的主要调节因子（由Ho & Glimcher综述，Cell 2002）。最近的工作表明，树突状细胞（DC）的亚群贡献显着的极化影响T辅助细胞分化。先天性和适应性免疫应答的结果都与DC衍生的细胞因子的不同特征直接相关。我们最近发现，T-bet控制骨髓来源和脾来源的DC产生炎性细胞因子IFN γ。因此，T-bet控制T细胞和NK细胞以及DC中的Th 1极化，并充当先天性和适应性免疫应答的主调节剂。然而，T-bet控制先天免疫系统细胞中I型免疫的机制尚不清楚。在拟议的研究中，我们将问（i）是什么调控了DC中的T-bet表达（具体目标1）;（ii）DC中T-bet的靶基因是什么？（具体目标2）和（iii）在病理状态的设置中，T-bet在DC中的功能是什么（具体目标3）。这些研究可能允许合理设计的代理，操纵相关的信号通路，在DC以及Th细胞，以提高1型免疫感染，并控制炎症，自身免疫性疾病和其他病理状态，具有更高的效率。

DESCRIPTION (provided by applicant): Differentiation from nave T helper (Th) cells into Th1 and Th2 subsets is an important process that determines the immune response to intracellular and or extracellular pathogens via the secretion of distinct cytokines. Transcription factors, c-Maf and GATA-3 direct Th2 lineage commitment, whereas T-bet, recently discovered in our laboratory, serves as a master regulator for Th1 cell differentiation (Reviewed by Ho & Glimcher, Cell 2002). Recent work suggests that dendritic cell (DC) subsets contribute significant polarizing influences on T helper differentiation. Outcomes of both innate and adaptive immune responses are directly related to the distinct profile of DC-derived cytokines. We have found recently that T-bet controls the production of the inflammatory cytokine IFNgamma from both marrow derived and splenic DCs. Thus, T-bet controls Th1 polarization both in T and NK cells as well as DCs, and acts as a master regulator of both innate and adaptive immune responses. However, the mechanisms by which T-bet controls Type I immunity in cells of the innate immune system are unknown. In the proposed studies, we will ask (i) what regulates T-bet expression in DCs (Specific Aim 1); (ii) what are the target genes for T-bet in DCs? (Specific Aim 2) and (iii) what are the functions of T-bet in DCs in the setting of pathological states (Specific Aim 3). These studies may permit the rational design of agents that manipulate the relevant signaling pathways, both in DCs as well as in Th cells, to enhance Type 1 immunity for infections, and to control inflammation, autoimmune diseases and other pathological states with much higher efficiency.