TLR-4 IN LIVER IMMUNOREGULATION

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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.