Mechanism of immune suppression induced by measles virus

人CD46，前身为膜辅助因子蛋白(MCP)，结合并灭活补体C3b，作为麻疹病毒(MV)的受体，从而保护细胞免受同源补体的感染，从而维持系统性麻疹感染。巨噬细胞(M-φ)通过交联CD46来抑制细胞免疫，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不清楚。在这里，我们发现经GM-CSF处理6-8天的外周血单核细胞获得了向CD46募集SHP-1的能力，并同时能够产生IL-12p40和一氧化氮(NO)。在同一时间内，Mφ获得了将CD9、Alphasβ整合素组装到CD46上的能力。成熟期较早的M-φ对病毒复制有促进作用，但在活化期，NO和细胞因子被诱导，病毒复制受到严重抑制。这些细胞反应需要C3b、mAbF(ab‘)2或MV H/F糖蛋白直接连接CD46，而不需要细胞内MV复制。有趣的是，KO株在GM-CSF6-8天培养的M-φ中不能复制，而其他MV株在相同条件下复制形成合胞体。当用KO株刺激时，SHP-1从CD46上迅速而瞬时地解离。综上所述，CD46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体。这些结果为CD46作为信号转导分子以及配体的性质决定天然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CD46信号转导。

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.