Tim-3抑制RIG-I 信号通路的分子机制及意义研究

Tim-3是广泛表达于免疫细胞，能抑制免疫细胞功能的新一代checkpoint分子。Tim-3在T细胞的高表达与感染性疾病的免疫耐受密切相关，被视为新的免疫治疗靶点。我们前期研究发现Tim-3抑制巨噬细胞中病毒识别受体RIG-I的转录及翻译后修饰，提示Tim-3还可能通过抑制天然免疫应答来诱导抗感染免疫耐受，但其分子机制及意义尚不清楚。RIG-I 作为在病毒识别及应答中发挥关键防御作用的模式识别受体，其调控机制近年来倍受关注。深入探讨Tim-3抑制RIG-I信号通路的机制将对全面认识Tim-3的调节功能，研发新的抗感染策略具有重要意义。在前期研究的基础上，本项目拟阐明：1）Tim-3 抑制RIG-I转录的分子机制；2）Tim-3调控RIG-I翻译后修饰的分子机制；3）Tim-3抑制巨噬细胞中RIG-I活性对机体抗病毒应答的影响，最终为Tim-3在抗感染免疫领域的应用提供新的理论及实验依据。

Tim-3 is a recently identified immune checkpoint inhibitor which is expressed on many immune cells. Dysregulated overexpression of Tim-3 on T cells is associated with T cell tolerance in infectious diseases, and it is now considered as a new therapeutic target for infectious diseases. Recently we found that Tim-3 inhibits the transcription and posttranslational modification of RIG-I, a critical pattern recognition receptor of virus, in macrophages, which indicated that Tim-3 might also induce infection tolerance by inhibiting the innate immunity. However, the underlying mechanism remain largely unclear. As a critical recognition receptor for virus, RIG-I play important roles in host defense against virus. And its regulation during infection are widely investigated recently. Identify the mechanisms by which Tim-3 inhibits RIG-I in macrophages will provide much needed insights both for understanding the roles of Tim-3 in immune regulation and for exploring new therapeutic strategy against infection. Based on our recent findings, here we will try to answer the following questions: 1) Find the mechanisms by which Tim-3 inhibits RIG-I transcription; 2) Find the mechanisms by which Tim-3 regulates post translational modification of RIG-I; 3) By using conditional knockout mice, try to demonstrate the effects of Tim-3 inhibition on RIG-I in macrophages on host immunity against infection.