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Mechanism of immune suppression induced by measles virus

麻疹病毒引起的免疫抑制机制

基本信息

批准号：
10470083
负责人：
SEYA Tsukasa
金额：
$ 3.2万
依托单位：
OSAKA MEDICAL CENTER FOR CANCER AND CARDIOVASCULAR DISEASES
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470083/
关键词：
measles virus human CD46 signal transduction SHP-1 CD9 α3 β1 integrin moesin immune suppression α_3β_1インテグリン麻疹ウィルス innate immunity(基本免疫)抗原提示細胞 IL-12 ホスファターゼ補体

项目摘要

Human CD46, formerly membrane co factor protein (MCP), binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity including down-regulation of IL-12 production has been reported on macrophages (Mφ) by crosslinking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. Here, we found that 6-8 day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and nitric oxide (NO). Within the same time frame, Mφ acquired the capacity to assemble CD9, alphaS betal integrin to their CD46. Mφ earlier to this maturation stage were able to potentiate MV (Edmonston and Nagahata strain) replication, but in the activation stage NO and cytokines were induced and MV replication was severely suppressed. Direct ligation of CD46 by C3b, mAbs F(ab')_2 or MV H/F glycoproteins, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6-8 day GM-CSF-cultured Mφ while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. Taken together, CD46 first serves as a receptor for MV, then recruits a molecular complex as depending upon maturation stages of human Mφ. These results provide strong evidence that CD46 serves as a signal-transducing molecule and that the properties of ligands determine suppression or activation of innate immune system. MV-mediated immune suppression may in part be attributable to the CD46 signaling.

人CD 46，以前称为膜辅因子蛋白（MCP），结合并灭活补体C3 b，并作为麻疹病毒（MV）的受体，从而保护细胞免受同源补体的侵害并维持全身性麻疹感染。已经报道了通过交联巨噬细胞（Mφ）的CD 46来抑制细胞介导的免疫，包括下调IL-12的产生。然而，负责这些免疫反应的细胞内事件仍然未知。在此，我们发现6-8天GM-CSF处理的外周血单核细胞获得了将SHP-1募集到其CD 46的能力，并且伴随地能够产生IL-12 p40和一氧化氮（NO）。在相同的时间范围内，Mφ获得了将CD 9、α S β 1整合素组装到它们的CD 46的能力。Mφ在此成熟阶段早期能够增强MV（Edmonston和Nagahata株）的复制，但在激活阶段，NO和细胞因子被诱导，MV复制被严重抑制。这些细胞应答需要C3 b、mAbs F（ab '）_2或MV H/F糖蛋白直接连接CD 46，而不是细胞内MV复制。有趣的是，KO株不能在GM-CSF培养的6-8天的Mφ中复制，而其他MV株在相同条件下复制形成合胞体。当用KO菌株刺激时，观察到SHP-1从CD 46快速和瞬时解离。总而言之，CD 46首先作为MV的受体，然后根据人Mφ的成熟阶段招募分子复合物。这些结果为CD 46作为信号转导分子以及配体的性质决定先天免疫系统的抑制或激活提供了强有力的证据。MV介导的免疫抑制可能部分归因于CD 46信号传导。