PDL1调控神经元与脑部浸润CTL细胞相互作用对脑型疟神经元的保护机制研究

脑型疟是恶性疟原虫感染的严重并发症，超过10%幸存者残留神经系统后遗症，发病机制尚不完全清楚。脑型疟血脑屏障损伤后脑实质炎症持续状态可能是神经组织损伤的重要原因。多种神经系统炎性疾病研究证实，脑部T细胞与神经元之间的相互作用在其发病机制中起关键作用。项目组发现：脑型疟晚期小鼠脑干有大量CD8+CTL细胞浸润，该CTL细胞可杀伤脑干神经元；且该小鼠脑干高表达PDL1神经元比例大幅增加，敲除小鼠I型干扰素受体基因后此现象消失。申请人推测：I型干扰素诱导神经元高表达PDL1，在PD1/PDL1免疫负调节通路调控下抵抗CTL细胞对神经元的杀伤，神经元与CTL细胞的相互作用及其结局对脑型疟是否发生神经组织损伤有重要影响。本项目以PDL1调控神经元与脑部浸润CTL细胞相互作用为重点，聚焦I型干扰素对神经元PDL1表达的调节及其信号通路研究，进一步阐明脑型疟神经组织损伤发病机制，探索免疫辅助治疗新方法。

Cerebral malaria, caused by Plasmodium falciparum, is one of the most serious complications of severe malaria with high mortality, and more than 10% of survivors have suffered neurological sequelae. So far, the potential pathogenesis is still not fully understood. Studies suggest that the persistent status of brain parenchymal inflammation caused by cerebral malaria after blood-brain barrier injury is the key mechanism contributing to nerve tissue damage. In recent years, studies on many neuroinflammatory diseases have confirmed that the interaction between brain-infiltrating T lymphocytes and neurons plays a key role in the pathogenesis. We have found that there are a large amount of infiltrating CD8+CTLs in the brainstem of mice with late stage cerebral malaria and the CTLs can exert cytotoxic effects on brainstem neurons. Furthermore, the proportion of neurons with PDL1 highly expressed in the mice brainstem increased significantly, while the changes can’t be detected in the mice with type I interferon receptor gene knocked out. So we hypothesize that type I interferon induces neurons to overexpress PDL1 to resist the cytotoxic effect of CTLs via PD1/PDL1 negative immunoregulatory signaling pathway and the outcome of interaction between neurons and CTLs have an important effect on whether severe nerve tissue damage will occur or not in cerebral malaria. Therefore, we focus on PDL1-regulated interaction between neurons and brain-infiltrating CTLs and aim at exploring molecular mechanism and key signaling pathway on type I interferon mediated-neuronal PDL1 expression, which is expected to further clarify the pathogenesis of nerve tissue damage caused by cerebral malaria and provide new research ideas for adjuvant immunotherapy of cerebral malaria.