Transcription Factor T-belt in Dendritic Cells

描述（由申请人提供）：nave T辅助性（Th）细胞分化为Th1和Th2亚群是一个重要的过程，通过分泌不同的细胞因子来决定对细胞内和/或细胞外病原体的免疫反应。转录因子c-Maf和gada -3直接参与Th2谱系，而最近在我们实验室发现的T-bet则是Th1细胞分化的主要调节因子（review by Ho & Glimcher, cell 2002）。最近的研究表明，树突状细胞（DC）亚群对辅助性T分化有显著的极化影响。先天性和适应性免疫反应的结果与dc来源的细胞因子的独特特征直接相关。我们最近发现T-bet可以控制来自骨髓和脾dc的炎性细胞因子IFNgamma的产生。因此，T-bet控制T细胞和NK细胞以及dc中的Th1极化，并作为先天和适应性免疫反应的主要调节剂。然而，T-bet控制先天免疫系统细胞I型免疫的机制尚不清楚。在拟议的研究中，我们将问(i)是什么调节了dc中的T-bet表达（Specific Aim 1）；（ii） dc中T-bet的靶基因是什么？（特异性目的2）和（iii）病理状态下dc中T-bet的功能（特异性目的3）。这些研究可能允许合理设计操纵dc和Th细胞中相关信号通路的药物，以提高对感染的1型免疫，并以更高的效率控制炎症、自身免疫性疾病和其他病理状态。

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.