Differentiation and Regulation of CTL

描述（由申请人提供）：T细胞介导的免疫应答需要T细胞和抗原（Ag）呈递细胞（APC）之间的接触依赖信息交换。幼稚T细胞是由成熟树突状细胞（DC）在次级淋巴器官（如外周淋巴结（PLN））中引发的。经过几天的激活后，增殖的T细胞分化为细胞毒性效应细胞（CTL）。可以杀死APCCTL活性被认为受多种机制控制，包括调节性T细胞（Treg）的作用和CTL在退出生存信号时发生凋亡的倾向。因此，在CTL反应达到高度后，Ag特异性T细胞池收缩，留下一小部分长寿命记忆细胞，当Ag返回时，它们的反应比初始T细胞更强烈。人们普遍认为，T细胞的职业决策受其表面相互作用的通讯分子的时空排列所调控

DESCRIPTION (provided by applicant): T cell-mediated immune responses require contact-dependent information exchange between T cells and antigen (Ag)-presenting cells (APC). Naive T cells are primed by mature dendritic cells (DC) in secondary lymphoid organs, such as peripheral lymph nodes (PLN). After a few days of activation, the proliferating T cells differentiate into cytotoxic effector cells (CTL). which can kill APC. CTL activity is thought to be controlled by several mechanisms, including the action of regulatory T cells (Treg) and the propensity of CTL to undergo apoptosis upon withdrawal of survival signals. Thus, after the height of a CTL response, the pool of Ag-specific T cells contracts, leaving behind a small population of long-lived memory cells, which respond more vigorously than naive T cells when the Ag returns. It is widely held that the career decisions taken by T cells are regulated by the spatio-temporal arrangement of interacting communication molecules on the surface of T cells and APC. However, the physical nature and the kinetics of T cell-APC interactions in PLN are still largely unexplored. In preliminary work for this project, we have developed a new multiphoton intravital microscopy (MP-IVM) model to study APC and TCR transgenic CDS T cells in intact popliteal LN of anesthetized mice. This imaging approach produces 3D time-lapse movies of interacting cells at subcellular resolution and will be used to address the following two specific aims: 1.) To analyze the spatial, temporal and behavioral relationship between CTL and APC in PLN and 2.) To explore the effect of Ag-specific Treg on CTL differentiation and function. The proposed experiments will generate a comprehensive, mechanism oriented analysis of CTL differentiation, function and regulation. This information may lead to improved strategies for clinical immunomodulation, e.g. for vaccinations, tumor therapy and treatment of infectious, inflammatory and autoimmune diseases.