T cell functional exhaustion in chronic infections and tumors limits effective immunity. Chronic hepatitis B virus (HBV) infection afflicts over 350 million people worldwide and over a million die from chronic HBV infection related diseases. Current treatments for CHB have various limitations and cannot cure most of the CHB patients. Virus-specific CD8+ T cells play an essential role in HBV suppression and clearance through cytolytic and non-cytolytic mechanisms. However, antigen-specific CD8+ T cells in CHB patients have functional exhaustion. In addition, large infiltrates of non-antigen-specific lymphocytes and monocytes in the livers of CHB patients are tightly associated with persistent inflammation and liver damage. These infiltrates of non-antigen-specific cells lead to chronic necroinflammatory liver disease and ultimately hepatocellular carcinoma. Thus, therapeutic approaches restoring exhausted T cells and removing the sequestered non- antigen-specific cells in the liver are necessary steps to achieve a complete cure of CHB. We have investigated CD8+ T cell exhaustion during chronic HBV infection and found that HBV antigen-specific CD8+ T cells are sequestered in the spleens of CHB patients and fail to expand upon antigen stimulation. Furthermore, we found that splenic HBV-specific CD8+ T cells and intrahepatic non-antigen specific CD8+ T cells exhibit reduced expression of S1PR1. We have identified a novel microRNA, miR-720, as a possible regulator of CD8+ T cell exhaustion during chronic HBV infection. MiR-720 expression was elevated in HBV-specific and total CD8+ T cells from CHB patients and its overexpression inhibits proliferation of normal primary human T cells. Furthermore, we have identified the cell proliferation related genes FosB and c-Myc as well as cell migration related gene S1PR1 as miR-720 target genes. Based on these findings, we hypothesize that HBV- induced upregulation of miR-720 in CD8+ T cells is an important determinant in the development of chronic HBV infection. We propose to test whether neutralizing miR-720 can rescue antigen-specific CD8+ T cell function and determine the role of S1PR1 in lymphocyte infiltration and liver damage. Furthermore, we will perform single cell gene expression analysis to elucidate the exhaustion pathways in HBV-specific CD8+ T cells in the context of miR-720 expression and identify the factors that regulate miR-720 expression. Answers to these questions will provide novel insights to the underlying molecular mechanisms of T cell exhaustion and may lead to new immunotherapeutic strategies for the treatment of CHB patients.
We propose to study how a novel microRNA regulates T cell functional exhaustion during chronic hepatitis B virus infection. The results from this study will provide important insights to the molecular mechanisms of T lymphocyte functional exhaustion and liver damage during chronic HBV infection. Importantly, given the rapid development of clinical application of microRNAs as therapeutic agents, our research may lead to the development of therapeutic agents targeting this novel microRNA and its target genes for the treatment of chronic HBV infection.
| Zhang, Hui; Wang, Yu; Hwang, E Shelley et al. (2016) Interleukin-10: An Immune-Activating Cytokine in Cancer Immunotherapy. J Clin Oncol 34:3576-3578 |
| Wang, Yu; Zhang, Zheng; Ji, Dong et al. (2015) Regulation of T cell function by microRNA-720. Sci Rep 5:12159 |
