Inflammatory Control of Lymphocyte Trafficking

描述（由申请人提供）：急性炎症反应的一个关键组成部分是血源性淋巴细胞迅速动员到次级淋巴器官。在保护性免疫启动过程中，这些器官是淋巴细胞与抗原和外来病原体接触的集结地。在定义引导淋巴细胞通过淋巴器官血管检查点的稳态运输的粘附事件方面取得了重大进展。相比之下，炎症期间诱导幼稚和中枢记忆细胞向淋巴器官运输的分子基础尚不清楚。大量的初步数据使我们假设促炎细胞因子，白细胞介素-6 (IL-6)，是在急性炎症期间调节淋巴细胞向淋巴器官迁移的驱动力。第一个目标是确定IL-6的细胞来源，IL-6调节全身发热性炎症模型中血管通道的捕获效率。与野生型和IL-6缺陷小鼠的互惠骨髓嵌合体将分离IL-6的产生是否需要抗辐射基质细胞或辐射敏感的造血细胞来增强淋巴细胞在热应激期间跨血管壁的运输。归巢试验和活体显微镜将进一步证实IL-6的特定细胞来源促进淋巴细胞流入淋巴样器官。目的2将侧重于确定IL-6是否也负责在适应性免疫反应中动员初始细胞募集到局部炎症淋巴结。这些研究是基于我们令人惊讶的发现，成熟树突状细胞产生的IL-6改变了血管入口通道的粘附特性。最终目的将使用遗传方法来剖析IL-6下游信号转导途径，这些信号转导途径在局部和全身适应性免疫反应中调节淋巴细胞运输。这些研究将使用在IL-6信号通路中具有特定缺陷的突变小鼠系，以便绘制急性炎症期间加速淋巴细胞运输所需的分子机制。了解急性炎症期间淋巴细胞募集的细胞因子需求可能会导致慢性炎症疾病的新干预策略，并为基于IL-6增强适应性免疫能力的疫苗方法提供见解。

DESCRIPTION (provided by applicant): A critical component of the acute inflammatory response is the rapid mobilization of blood- borne lymphocytes into secondary lymphoid organs. These organs are the staging ground for lymphocyte encounters with antigens and foreign pathogens during the initiation of protective immunity. Significant progress has been achieved in defining the adhesion events that guide homeostatic steady-state trafficking of lymphocytes across vascular checkpoints in lymphoid organs. By contrast, the molecular basis of inducible trafficking of naive and central memory cells to lymphoid organs during inflammation is poorly understood. Extensive preliminary data lead us to hypothesize that the proinflammatory cytokine, interleukin-6 (IL-6), is a driving force in regulating lymphocyte migration into lymphoid organs during acute inflammation. The first aim will identify the cellular source of IL-6 that regulates the capture efficiency of vascular gateways in a model of systemic febrile inflammation. Reciprocal bone marrow chimeras with wild-type and IL-6-deficient mice will segregate whether IL-6 production by radiation-resistant stromal cells or radiation-sensitive hematopoietic cells is required for enhanced lymphocyte trafficking across vessel walls during febrile stress. Homing assays and intravital microscopy will further validate that a defined cellular source of IL-6 promotes lymphocyte influx into lymphoid organs. Aim 2 will focus on determining if IL-6 is also responsible for mobilizing the recruitment of naive cells to local inflamed lymph nodes during an adaptive immune response. These studies are based on our surprising discovery that IL-6 produced by mature dendritic cells modifies the adhesive properties of vascular entryways. The final aim will use genetic approaches to dissect the IL-6 downstream signal transduction pathways that regulate lymphocyte trafficking during local and systemic adaptive immune responses. The studies will use mutant mouse lines that have specific defects in IL-6 signaling pathways in order to map the molecular mechanisms required for accelerated lymphocyte trafficking during acute inflammation. Understanding the cytokine requirements for lymphocyte recruitment during acute inflammation may lead to novel intervention strategies in chronic inflammatory disorders as well as provide insights into vaccine approaches based on the ability of IL-6 to heighten adaptive immunity. PUBLIC HEALTH RELEVANCE: This proposal addresses fundamental questions in immunology regarding the mechanisms governing trafficking of lymphocytes to lymphoid organs during acute inflammation, a function that is crucial for host protection against pathogens. The molecular mechanisms that mediate basal trafficking of lymphocytes to lymphoid organs are well defined, however, little is known about the means of augmenting lymphocyte trafficking during acute inflammation. The proposed studies are expected to provide important insights into the unique role of cytokines in dynamically regulating leukocyte trafficking at key vascular checkpoints. These studies further have the potential to lead to novel therapeutic targets for the promotion of immune surveillance as well as for the treatment of chronic inflammation.