TLR-4 In Liver Immunoregulation

肝脏有能力将激活的CD8 T细胞从循环池中隔离出来，部分原因是肝窦内皮细胞上表达了黏附分子。然而，这种隔离的详细机制及其在免疫反应方面的意义都是未知的。我们最近做了一个惊人的观察，在缺乏TLR-4分子的小鼠中，激活的T细胞在肝脏中的优先聚集丢失了。肝脏中缺乏TLR-4会影响急性免疫反应和CD8 T细胞记忆，基于Affymetrix阵列的正常肝脏和TLR-4缺陷肝脏的比较发现，CXCL1是TLR-4和细胞黏附机制之间联系的主要候选者。在特定的目标1中，我们将测试肠道细菌、库普弗细胞和MyD88与TRIF信号通路在促进TLR-4依赖的肝脏捕获方面的重要性。在特定的目标2中，我们将测试CXCL1的来源和意义，并确定它通过哪些下游途径调节细胞黏附。这项研究将确定肝脏在系统CD8免疫和记忆形成中的作用。抑制肝脏调节T细胞记忆的能力可能是提高疫苗有效性的一种方式。 PHS 398/2590(11/07版) 页面 续订格式页面

The liver has a capacity to sequester activated CD8+ T cells from the circulating pool, due in part to the expression of adhesion molecules on the hepatic sinusoidal endothelium. However, both the detailed mechanisms responsible for this sequestration and its significance in terms of immune responses are unknown. We recently made the striking observation that in mice that lack the TLR-4 molecule, the preferential accumulation of activated T cells in the liver is lost. The lack of TLR-4 in the liver affects both acute immune responses and CD8+ T cell memory, and an Affymetrix array-based comparison of normal and TLR-4-deficient liver has identified CXCL1 as a prime candidate for the link between the TLR-4 and cell adhesion mechanisms. In Specific Aim 1 we will test the importance of intestinal bacteria, Kupffer cells, and the MyD88 versus TRIF signaling pathways in promoting TLR-4 dependent liver trapping. In Specific Aim 2 we will test the source and significance of CXCL1 and determine through which downstream pathways it modulates cell adhesion. This research will define the role of the liver in systemic CD8+ immunity and memory formation. Inhibiting the liver's capacity to modulate T cell memory may be a way to enhance the effectiveness of vaccines. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page