HCV is adept at setting up long term persistence and has evolved a number of strategies to evade the host T cell response. Cellular immune responses, mediated by T cells, both CD4+ and CD8+ play a very important role in host protection. In terms of evasion of such responses, 2 major mechanisms have been proposed - firstly escape through viral mutation;secondly some form of downregulatory mechanism, potentially exhaustion of the T cell response or mediated by regulatory T cell subsets. However, these fail to address the key feature of HCV, namely its hepatotropism, which may be central to the development of tolerance and failure of immunity. In this study, we aim to build upon recent data that is beginning to define a new area of the biology of T cell maturation, focusing on a novel marker for antiviral T cells, CD161 (KLRB1/NKR-P1A), which is expressed selectively on HCV specific and HBV specific cells. CD161 can deliver inhibitory signals to CD8+ T cells when it encounters its ligand LLT1 (expressed on hepatocytes);it is also tightly associated with the expression of a known critical chemokine receptor CXCR6, which binds CXCL16 expressed within the hepatic sinusoid. CD161 bright cells display a distinct phenotypic and functional profile, with strong secretory but limited cytolytic capacity. There is also a drastic loss of CD161 bright/CXCR6+ cells from the blood of HCV+ donors (14.7% vs 3.4%, p<0.0001). There are three specific aims: 1. To define the functional and phenotypic profile of liver homing CD8+ T cells in healthy and HCV+ donors;2. To define the profile of CD4 T cells associated with liver homing and address the role of CD161and CXCR6 on this subset;3: To define the functional impacts of signalling through key surface receptors on CD161 (CXCR6+) bright and dim cells and their ligands. In collaboration with the other team members these aims will be achieved through molecular profiling of sorted subsets of CD8+ T cells from blood and liver in health and disease. Candidate molecules will be screened using MHC Class I and Class II tetramer staining with appropriate disease controls. The impact of ligation of CD161/CXCR6 and novel linked molecules will be ascertained using polychromatic flow cytometry, and transcriptional profiling and the in vivo relevance of such pathways will be sought at the site of disease - the liver itself.
HCV affects about 170 million people worldwide and is a major cause of liver disease. HCV is adept at setting up long term persistence and has evolved a number of strategies to evade the host T cell response. We will define molecular pathways that are both disease specific and relate to chronic inflammation in the liver. This is of substantial relevance to other infectious processes and will provide a model to prevent and treat organ-specific immunologic tissue damage in this and other emerging infectious diseases of man.
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