TLR-4 IN LIVER IMMUNOREGULATION

与公共卫生的相关性。该项目旨在了解肝脏如何控制免疫 应答这种理解将是宝贵的，因为它将使我们能够提高 疫苗。 技术摘要。肝脏有能力隔离活化的CD 8 + T细胞， 部分由于肝窦内皮上粘附分子的表达， 然而，无论是负责这种粘附的机制，还是这一过程的重要性， 系统性免疫应答是可以理解的。最近我们发现了模式识别受体TLR-4， 作为这个过程中的关键角色。因此，TLR-4缺陷的肝脏不能隔离活化的CD 8 + T细胞， 导致增加的系统性初级和记忆T细胞应答。这个过程是由LPS驱动的， 肠道细菌，信号通过MyD 88途径介导。一个Affyphonian阵列屏幕 确定CXCL 1作为传递TLR-4效应的主要候选者，尽可能与CD 36和PDE 4一起 替代品.在特定目标1中，我们将测试TLR-4及其下游效应子在哪个细胞群中 分子在肝内CD 8 + T细胞捕获期间起作用。在具体目标2中，我们将测试CXCL 1 途径和几种替代机制，以确定哪些是重要的。在第三阶段，我们将测试 TLR-4依赖性肝脏捕获CD 8 + T细胞在全身免疫应答中的意义 流感病毒，并专门测试对T细胞记忆和二级保护的影响。如果TLR-4- 依赖性CD 8 + T细胞肝内捕获途径可以理解，这可以用来增强 使用CD 8 + T细胞的过继免疫疗法。如果它影响了二级免疫保护， 也可以有针对性地提高弱疫苗的有效性。

RELEVANCE TO PUBLIC HEALTH. This project seeks to understand how the liver controls immune responses. This understanding will be valuable because it will enable us to improve the effectiveness of vaccines. TECHNICAL ABSTRACT. The liver has the capacity to sequester activated CD8+ T cells from the circulation, due in part to the expression of adhesion molecules on the liver sinusoidal endothelium. However, neither the mechanisms responsible for such adhesion, nor the significance of this process in systemic immune responses are understood. Recently we identified the pattern-recognition receptor, TLR-4, as a key player in this process. Thus, TLR-4 deficient livers failed to sequester activated CD8+ T cells, resulting in increased systemic primary and memory T cell responses. This process was driven by LPS from the intestinal bacteria, and signals were mediated through the MyD88 pathway. An Affymetrix array screen identified CXCL1 as a prime candidate for delivering the TLR-4 effect, with CD36 and PDE4 as possible alternatives. In Specific Aim 1 we will test in which cell population the TLR-4 and its downstream effector molecules are acting during intra-hepatic CD8+ T cell trapping. In Specific Aim 2, we will test the CXCL1 pathway and several alternative mechanisms to determine which is important. In Specific Aim 3, we will test the significance of TLR-4-dependent liver trapping of CD8+ T cells during the systemic immune response to influenza virus, and specifically test the impact on T cell memory and secondary protection. If the TLR-4- dependent CD8+ T cell intra-hepatic trapping pathway can be understood, this could be exploited to enhance adoptive immunotherapy using CD8+ T cells. If it impacts on secondary immune protection, this pathway could also be targeted to improve the effectiveness of weak vaccines.