Inflammatory Control of Lymphocyte Trafficking

急性炎症反应的一个关键组成部分是血液的快速动员- 携带的淋巴细胞进入次级淋巴器官。这些器官是集结地 对于淋巴细胞在启动过程中与抗原和外来病原体的接触 保护豁免权。在确定粘连事件方面取得了重大进展 引导淋巴细胞通过血管检查站的动态平衡稳态运输 淋巴器官。相比之下，NA和Central可诱导转运的分子基础 在炎症过程中，记忆细胞到淋巴器官的作用还知之甚少。广泛性 初步数据使我们假设促炎细胞因子，白介素6(IL-6)， 是调节淋巴细胞向淋巴器官迁移的驱动力 发炎。第一个目标是确定调节捕获的IL-6的细胞来源 全身性发热性炎症模型中血管通道的有效性。对偶骨 野生型和IL-6缺陷小鼠的骨髓嵌合体将分离IL-6 抗辐射的基质细胞或辐射敏感的造血细胞产生的 在发热应激期间增强淋巴细胞跨血管壁运输所必需的。 归巢分析和活体显微镜将进一步验证确定的细胞来源 IL-6促进淋巴细胞进入淋巴器官。目标2将专注于确定IL-6是否 还负责动员NA细胞向局部发炎的淋巴结处募集 在适应性免疫反应中。这些研究是基于我们的发现，IL-6 由成熟的树枝状物质产生，改变血管入口的粘附性。这个 最终目的将使用遗传学方法来剖析IL-6下游信号转导 局部和全身适应性免疫过程中调节淋巴细胞转运的途径 回应。这些研究将使用在IL-6中有特定缺陷的突变小鼠品系 信号通路，以映射加速所需的分子机制 急性炎症期间淋巴细胞的运输。了解细胞因子的需求 急性炎症期间淋巴细胞募集可能导致新的干预措施 治疗慢性炎症性疾病的策略以及对疫苗的见解 基于细胞因子提高获得性免疫能力的方法。

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 na¿ve 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 na¿ve cells to local inflamed lymph nodes during an adaptive immune response. These studies are based on our discovery that IL-6 produced by mature dendritic 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. These studies will use mutant mouse lines that have specific defects in IL-6 signaling pathways in order to map the molecular mechanism 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 cytokines to heighten adaptive immunity.