TLR-4 In Liver Immunoregulation

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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