IL-6阻断IL-2/CD122信号通路影响双阴性T细胞功能促进PBC发病的研究

双阴性T（Double Negative T, DNT）细胞对维持肝脏稳态具有重要作用，其存活及免疫调节功能依赖IL-2。我们发现原发性胆汁性胆管炎（Primary biliary cholangitis, PBC）患者IL-2升高但DNT数量及功能缺陷，这主要与CD122表达下降有关。我们还发现IL-6可下调CD122表达导致DNT对IL-2低反应，但其具体机制及CD122下游调控DNT存活及功能的关键信号仍不清楚。因此，本研究将以CD122为靶点，首先明确CD122对DNT细胞IL-2抵抗状态的影响，其次探讨CD122及其下游PIK3R1信号对自身存活及抑制功能的调控；然后阐明IL-6调控DNT细胞CD122表达及其可能机制；最后在PBC小鼠中验证CD122对DNT存活及免疫抑制功能的影响，并过继转移CD122+/-的DNT细胞探讨其对PBC小鼠治疗差异，以期为PBC的防治提供新证据。

Double negative T (DNT) cells play an important role in maintaining liver homeostasis. Their survival and immune regulation function depend on IL-2. However, we found an elevated IL-2 production but a defect number and function of DNT in patients with primary biliary cholangitis (PBC), which was induced by decreased CD122 (IL2R) expression on DNT cells. We also found that IL-6 can down regulate the CD122 on DNT, inhibiting the response to IL-2, but its specific mechanism and the key signal of CD122 downstream of DNT are still unclear. Therefore, we focus on CD122 in our study. First, we plan to clarify the role of CD122 on DNT cell resistance to IL-2. Then we are ready to explore the regulation of CD122 and its downstream PIK3R1 signal on its own survival and inhibition function of DNT; next, we will further clarify the possible mechanism of defective CD122 expression induced by IL-6 on DNT; finally, we will verify the effect of CD122 on DNT in PBC mice, and adoptively transfer CD122 + / - DNT in treatment of PBC mice, hoping to provide new strategies for the prevention and treatment of PBC.