肝脏微环境对CD8+T细胞活化和功能的抑制，是慢性HBV感染中病毒持续存在的重要原因。最近的研究显示，改善线粒体能量代谢能够恢复特异性CD8+T细胞的功能，提示能量代谢是HBV免疫治疗的潜在靶标。我们的前期工作发现，TLR2通路的激活诱导CD8+T细胞表达一系列能量代谢相关基因，增强细胞活化和功能。这提示我们，激活TLR2通路能够通过上调代谢调节因子IRF4/BATF提高能量代谢，使CD8+T细胞抵抗肝脏免疫抑制，维持肝内抗病毒功能。本项目将研究TLR2通路对能量代谢的调节，是否有利于CD8+T细胞抵抗肝脏原代细胞的免疫抑制；分析参与这一效应的关键调节分子和代谢途径；利用慢性HBV小鼠的过继治疗模型，评估CD8+T细胞能量代谢的调节对其肝内抗病毒功能和病毒清除的影响。本项目将揭示TLR2通路，能量代谢，肝脏免疫抑制，CD8+T细胞功能之间的内在联系，为HBV的免疫治疗提供新的思路和策略。

Therapeutic restoration of HBV-specific CD8+ T cell responses is considered as a potential strategy to treat chronically HBV-infected (CHB) patients. However, the immune tolerance mediated by liver parenchymal cells and nonparenchymal cells limits the antiviral activity of HBV-specific CD8+ T cells in the liver. Recent studies in CHB patients suggested that the functional exhaustion of HBV-specific CD8+ T cells is closed related to mitochondrial dysfunction and is able to be reversed by treatment of mitochondria-targeted antioxidants, suggesting a possibility to resist the immune tolerance by energy metabolism enhancement. Our previous studies showed that TLR1/2 agonist induce a series of energy metabolism-related genes, including transcription factors and enzymes, in CD8+ T cells, and ultimately improved CD8+ T cell activation and function. Therefore, we presume that activation of TLR2 signal pathway improves the expression of metabolic regulators IRF4/BATF, and thus increases the energy metabolism in activated CD8+ T cells, which is benefitial for the resistance to liver-induced immune tolerance and improvement of the anti-viral immune response. In this project, we will firstly investigate whether the TLR2 enhanced energy metabolism counteracts the functional inhibition of CD8+ T cell induced by liver cells. Secondly, we will try to identify the key regulators and metabolic pathways which involved in the TLR2-induced functional activation of CD8+ T cells and resistance to tolerance induction. Thirdly, we will evaluate the possibility to explore TLR2-induced metabolism activation in improving intrahepatic antiviral CD8+ T cell response in the HBV mouse model and T cell transfer experiments. Our approach will reveal the relationship between TLR2 signal pathway, energy metabolism, intrahepatic immune tolerance and CD8+ T cell function, and may provide new tools for developing effective antiviral therapy and immune modulatory treatments.