TLR-4 IN LIVER IMMUNOREGULATION

与公共卫生的相关性。这个项目试图了解肝脏是如何控制免疫的。 回应。这一理解将是有价值的，因为它将使我们能够提高 疫苗。 技术摘要。肝脏有能力将激活的CD8+T细胞从 循环，部分是由于肝窦内皮细胞上黏附分子的表达。 然而，无论是造成这种粘连的机制，还是这一过程在 系统免疫反应是可以理解的。最近我们发现了模式识别受体TLR-4， 作为这一过程中的关键参与者。因此，TLR-4缺陷的肝脏无法隔离激活的CD8+T细胞， 导致全身性初级和记忆性T细胞反应增加。这一过程是由脂多糖推动的 肠道细菌和信号是通过MyD88途径介导的。Affymetrix阵列屏幕 确定CXCL1是传递TLR-4效应的首选方案，尽可能使用CD36和PDE4 另类选择。在具体目标1中，我们将测试TLR-4及其下游效应器在哪个细胞群中 分子在肝内CD8+T细胞捕获过程中起作用。在特定目标2中，我们将测试CXCL1 途径和几个可供选择的机制来确定哪一个是重要的。在具体目标3中，我们将测试 TLR-4依赖的肝捕获CD8+T细胞在机体免疫应答中的意义 流感病毒，并专门测试对T细胞记忆和二次保护的影响。如果TLR-4- 可以理解依赖的CD8+T细胞肝内捕获途径，这可以被利用来增强 CD8+T细胞过继免疫治疗。如果它影响二次免疫保护，这条途径 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.