PDL1 Fusion Protein Protects Against Experimental Cerebral Malaria via Repressing Over-Reactive CD8+ T Cell Responses
PDL1 Fusion Protein Protects Against Experimental Cerebral Malaria via Repressing Over-Reactive CD8+ T Cell Responses
复制标题
PDL1 融合蛋白通过抑制过度反应的 CD8( ) T 细胞反应来预防实验性脑疟疾
DOI：
10.3389/fimmu.2018.03157
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发表时间：
2019-01-14
影响因子：
7.3
通讯作者：
Yang, Kun
中科院分区：
文献类型：
--
作者：
Wang, Jun;Li, Yue;Yang, Kun
脑型疟疾（CM），主要由恶性疟原虫（P.f.）引起，是严重疟疾最致命的并发症之一。由于脑浸润性CD 8（+）T细胞介导的免疫病理学是CM的主要发病机制，临床上没有安全有效的治疗方法集中在CD 8（+）T细胞上。需要新的方法来保护宿主免受伤害。有证据表明，程序性死亡-1（programmed death-1，PD-1）是最有效的免疫调节分子之一，因此我们构建了两种可溶性融合蛋白PDL 1-IgG 1Fc和PDL 2-IgG 1Fc，以增强先天性和适应性免疫细胞（包括巨噬细胞和CD 8（+）T细胞）的PD-1/PDL信号通路。首先，我们证实PD-1信号通路缺陷导致PD-1缺陷（Pdcd 1（-/-））小鼠中CD 8（+）T细胞增殖水平高于WT小鼠，生存时间较短。其次，PDL 1-IgG 1Fc处理的小鼠比对照组表现出更长的存活时间。此外，观察到PDL 1-IgG 1Fc通过限制实验性脑疟疾（ECM）期间过度反应的CD 8（+）T细胞的细胞毒性来改善血脑屏障（BBB）破坏。进一步的研究发现，PDL 1-IgG 1Fc处理的巨噬细胞显示出显著的抑制巨噬细胞M1极化及其对CD 8（+）T细胞的抗原呈递能力。总之，我们的研究结果表明，在ECM发病前的早期阶段给予PDL 1-IgG 1Fc对维持脑内免疫微环境稳态具有明显作用，并被认为是未来预防CM的有希望的候选药物。
Cerebral malaria (CM), mainly caused by Plasmodium falciparum (P. f.), is one of the most lethal complications of severe malaria. As immunopathology mediated by brain-infiltrating CD8(+) T cells is the major pathogenesis of CM, there is no safe and efficient treatment clinically focused on CD8(+) T cells. New methods are needed to protect the host from injury. As evidence has shown that programmed death-1 (PD-1) is one of the most efficient immunomodulatory molecules, we constructed two soluble fusion proteins, PDL1-IgG1Fc and PDL2-IgG1Fc, to enhance PD-1/PDL signaling pathways in innate and adaptive immune cells, including macrophages and CD8(+) T cells. Firstly, we confirmed that PD-1 signal pathway deficiency led to higher levels of CD8(+) T cell proliferation and shorter survival time in PD-1-deficient (Pdcd1(-/-)) mice than WT mice. Secondly, PDL1-IgG1Fc-treated mice exhibited a more prolonged survival time than control groups. Moreover, PDL1-IgG1Fc was observed to ameliorate blood-brain barrier (BBB) disruption by limiting the over-reactive CD8(+) T cell cytotoxicity during experimental cerebral malaria (ECM). Further studies found that PDL1-IgG1Fc-treated macrophages showed significant suppression in macrophage M1 polarization and their antigen presentation capability to CD8(+) T cells. In conclusion, our results demonstrated that the administration of PDL1-IgG1Fc in the early stage before ECM onset has an obvious effect on the maintenance of immune microenvironment homeostasis in the brain and is deemed a promising candidate for protection against CM in the future.