Wnt通路介导的树突状细胞调控记忆性T细胞增殖分化及诱导免疫耐受的机制研究

Memory T cells is one of the major obstacles in inducing transplantation tolerance, Wnt pathway is the key pathway in regulation of TMs formation and memory immune responses, but the activation mechanism of the Wnt pathway of TMs is still unclear. Dendritic cells (DCs)are the most effective antigen presenting cells in intial T-cells (TNs) activation. During recent years, many studies have shown that DCs dynamically expressed Wnt proteins. In this study, we suppose that DCs which dynamically expressed Wnt proteins may regulate the differentiation, maintenance, survival and apoptosis of TMs. Our previous studies have confirmed that tolerogenic DCs can induce the TMs immune tolerance, suggesting that Wnt pathway may be the effective pathway of tolerogenic DCs inducing TMs immune tolerance. In this study, we will establish the cell model and skin transplantation model, use technology of siRNA, gene transfection, flow cytometry, western blot,co-immunoprecipitation and so on, to prove our hypothesis, from molecules level to cells and overall levels. These results will provide new ideas and methods for inducing immune tolerance of the transplant recipients, and also for the treatment of autoimmune diseases, parasitic infections, cancers and so on.

记忆性T细胞(TMs)是诱导移植耐受的主要障碍之一，Wnt通路是调控TMs的形成和介导记忆免疫应答的关键通路。但活化TMs Wnt通路的机制不详。树突状细胞(DCs)是活化初始性T细胞(TNs)最有效的抗原提呈细胞。近年研究显示，DCs动态表达Wnt蛋白。本课题中，我们假设：在免疫应答中，动态表达Wnt蛋白的DCs可能是调控TMs分化增殖、维持、存活或凋亡的关键机制之一。我们前期研究证实：致耐受DCs有效诱导TMs的低反应性，据此假设：Wnt通路可能是致耐受DCs诱导TMs免疫耐受的有效通路之一。本课题通过建立细胞模型和皮肤移植模型，应用siRNA，基因转染，流式，Western blot，免疫共沉淀等技术，从分子-细胞-整体层次证明我们的假设。本研究结果将为诱导移植受者免疫耐受提供新的思路和途径，也可为自身免疫性疾病、寄生虫感染等疾病的治疗所借鉴，还可为肿瘤等疾病的治疗提供研究思路。

供器官严重不足、临床移植排斥治疗方案不能确保极少数有幸得到供器官的移植受者及移植物长期、有功能存活的情况下，诱导受者对移植物特异性免疫耐受是目前器官移植界的世纪难题和不懈追求。记忆性T细胞(Memory T cells, TMs)能迅速介导排斥反应，且现有免疫抑制方案不能有效抑制TMs介导的排斥反应，TMs已成为诱导移植耐受的主要障碍之一。本项目阐明了树突状细胞（Dendritic cells, DCs）对TMs形成、活化增殖、维持、存活或凋亡，以及介导记忆免疫应答的作用和机制，证实了Wnt3a和Wnt5a基因介导的β-catenin/TCF信号通路转录激活是其中一条重要的途径。这将为器官移植、肿瘤、自身免疫性疾病、寄生虫感染等疾病的治疗提供新的思路和途径。