Mechanism of immune suppression induced by measles virus

人CD46，前身为膜辅因子蛋白（MCP），结合补体C3b并使其失活，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，维持全身性麻疹感染。据报道，通过交联巨噬细胞（Mφ）的CD46可以抑制细胞介导的免疫，包括下调IL-12的产生。然而，导致这些免疫反应的细胞内事件仍然未知。在这里，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CD46的能力，同时能够产生IL-12 p40和一氧化氮（NO）。在相同的时间框架内，Mφ获得了将CD9、alpha α α整合素组装到CD46上的能力。早于该成熟阶段的Mφ能够促进MV （Edmonston和Nagahata菌株）的复制，但在激活阶段，NO和细胞因子被诱导，MV复制受到严重抑制。这些细胞反应需要C3b、单克隆抗体F（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菌株在gm - csf培养的6-8天的Mφ中未能复制，而其他MV菌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与CD46的快速和短暂分离。综上所述，CD46首先作为MV的受体，然后根据人类Mφ的成熟阶段招募分子复合物。这些结果提供了强有力的证据，证明CD46作为一种信号转导分子，并且配体的特性决定了先天免疫系统的抑制或激活。mv介导的免疫抑制可能部分归因于CD46信号。

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.