NLRC3通过调节T细胞增殖分化诱导肝移植术后免疫耐受的机制研究

Immune tolerance of liver grafts after liver transplantation is of great importance to the prognosis of the recipients, and T cell proliferation and differentiation is one of the key ways to induce immune tolerance, but its specific mechanism has not yet been clarified. Our previous study found that the mRNA expression level of NLRC3 was significantly up-regulated in CD4+ T cells in patients with clinically operative tolerance after liver transplantation, while the activation level of PI3K-mTOR was significantly decreased. Combined with relevant literatures, we speculate that NLRC3 in CD4+ T cells may induce immune tolerance of liver graft by inhibiting the activation and proliferation of naive T cells via PI3K-mTOR signaling pathway. Based on our previous studies, we intend to analyze the relationship among NLRC3 and PI3K-mTOR signaling pathway and liver graft tolerance in the collected clinical specimens. We will observe the influence of the differential expression of NLRC3 on the immune tolerance of liver graft in the established model of rat liver transplantation. To explore the relationship among NLRC3 and PI3K-mTOR signaling pathway and the proliferation and differentiation of T cells and its molecular mechanism, we will culture rat primary naive T cells and regulate the expression levels of NLRC3 and PI3K. This study will help to explore the mechanism of immune tolerance in liver transplantation.

肝移植术后移植肝免疫耐受对受体的预后具有重要意义，而T细胞的增殖分化是诱导免疫耐受的关键途径之一，但具体机制尚未阐明。我们前期研究发现，肝移植术后临床操作性耐受患者CD4+T细胞中NLRC3的mRNA表达显著上调，而PI3K-mTOR活化水平显著降低。结合相关文献，我们推测CD4+T细胞内的NLRC3可能通过调控PI3K-mTOR信号通路抑制初始T细胞的活化增殖，诱导形成移植肝免疫耐受。本项目拟在前期研究的基础上，在收集的临床标本中，分析NLRC3及PI3K-mTOR信号通路与移植肝耐受的相关性；在建立的大小鼠肝移植模型上，观察NLRC3的差异性表达对移植肝免疫耐受的影响；体外培养大鼠原代初始T细胞，分别调控NLRC3和PI3K的表达水平，探讨NLRC3与PI3K-mTOR信号通路激活及T细胞增殖分化的关系及分子机制。本课题实施将有助于深入了解肝移植免疫耐受的机制。

肝移植术后移植肝免疫耐受对受体的预后具有重要意义，而T细胞的增殖分化是诱导免疫耐受的关键途径之一，但具体机制尚未阐明。我们前期研究发现，肝移植术后临床操作性耐受患者CD4+T细胞中NLRC3的mRNA表达显著上调，而PI3K-mTOR活化水平显著降低。结合相关文献，我们推测CD4+T细胞内的NLRC3可能通过调控PI3K-mTOR信号通路抑制初始T细胞的活化增殖，诱导形成移植肝免疫耐受。本项目拟在前期研究的基础上，在收集的临床标本中，分析NLRC3及PI3K-mTOR信号通路与移植肝耐受的相关性；在建立的大小鼠肝移植模型上，观察NLRC3的差异性表达对移植肝免疫耐受的影响；体外培养大鼠原代初始T细胞，分别调控NLRC3和PI3K的表达水平，探讨NLRC3与PI3K-mTOR信号通路激活及T细胞增殖分化的关系及分子机制。本课题实施将有助于深入了解肝移植免疫耐受的机制。