Galectin-9-C/Tim-3信号通路在肺移植BOS中的作用及机制研究

T cells actively participate in the occurrence and development of BOS. Regulation of T cells is a crucial factor for preventing BOS damage. Galection-9 contains two different recognition domains, located in N- and C- terminal regions respectively. The two domains, Galectin-9-N and Galectin-9-C, can play different roles independently: Galectin-9-C mainly plays a role in induction of T cell apoptosis; whereas Galectin-9-N is mostly responsible for activation of innate immune cells. Galectin-9-C/Tim-3 signal pathway is a specific negative regulator of T cell immunity pathway. Our previous study showed that Tim-3+T cells were highly expressed in the transplanted lungs, which might be due to the activation of cell cycle.This research will clarify the correlation between Galectin-9, Tim-3 expression and BOS using the established mouse model of lung transplantation. Briefly, the approach will be first construct Galectin-9-C protein with three-dimensional conformation; then transfect the donor lungs to induce high expression of Galectin-9-C. Assays will be conducted to confirm that it can inhibit the activation of Tim-3+T cells, thereby inhibit rejection and decrease the occurrence and development of BOS. Through this approach we can validate the pathways that mediate Tim-3+T cell FOXO1a/3a up and increase P15INK4b, inhibit the activity of CDK4/6-CyclinD complexes, resulting in Tim-3+T cells cycle arrested in G1 phase and mediated immune suppression.

T细胞积极参与BOS发生发展, 调控T细胞是避免BOS损伤重要因素。研究表明 Galectin-9有两个不同结构域：Galectin-9的C端和N端，可独立发挥作用，Galectin-9-C主要是诱导T细胞凋亡，Galectin-9-C/Tim-3信号通路是一种特异性负调节T细胞免疫通路。课题组前期研究发现：Tim-3+T细胞在移植肺组织中高表达, 其可能是通过激活细胞周期而被激活。本课题通过建立小鼠肺移植模型，明确Galectin-9和Tim-3表达与BOS相关性；构建Galectin-9-C空间三维构象及其蛋白，转染供肺，使其高表达Galectin-9-C，确认其可抑制激活Tim-3＋T细胞，从而抑制排斥减弱ＢＯＳ；证明其通路介导Tim-3+T细胞FOXO1a/3a增加，上调P15INK4b，抑制CDK4/6-CyclinD复合物活性，导致Tim-3+T细胞阻滞于G1期，介导免疫抑制

肺移植是治疗终末期肺部疾病的有效方法，但肺移植现状仍然不能令人满意。闭塞性细支气管炎综合征（Bronchiolitis Obliterans Syndrome BOS ）是影响肺移植术后长期存活的最主要并发症。器官移植术后BOS的发生发展的机制极为复杂，但T、B淋巴细胞是介导移植排斥反应的关键效应细胞，CD4 + T和CD48+ T淋巴细胞在同种排斥中发挥着关键性作用，并随着植入时间的延长和排斥强度的增加呈上升趋势。同时我们发现B淋巴细胞在移植免疫反应中发挥多方面调节作用：B淋巴细胞及其效应因子积极参与慢性排斥反应的发生发展，可以明确它们是慢性排斥反应发生进展中的重要调节靶点。