MFG-E8 regulates the immunogenic potential of dendritic cells primed with necrotic cell-mediated inflammatory signals.
MFG-E8 regulates the immunogenic potential of dendritic cells primed with necrotic cell-mediated inflammatory signals.
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DOI：
10.1371/journal.pone.0039607
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jinushi M
中科院分区：
文献类型：
--
作者：
Baghdadi M;Chiba S;Yamashina T;Yoshiyama H;Jinushi M
树突状细胞(DC)通过识别死亡细胞和控制免疫功能来操纵组织的动态平衡。然而，DC识别不同类型的死亡细胞并设计出不同的免疫后果的确切机制在很大程度上仍然不清楚。在此，我们证明乳脂球-EGF VIII(MFG-E8)是控制炎症微环境中DC免疫原性的关键介质。MFG-E8抑制DC介导的对坏死细胞的摄取和识别。MFG-E8介导的DC对坏死细胞摄取的抑制导致促炎细胞因子的产生减少，并激活了信号成分STAT3和A20，这些信号成分对维持DC的耐受特性至关重要。此外，DC来源的MFG-E8在识别坏死细胞时负向调节抗原特异性T细胞的交叉启动和效应功能。MFG-E8缺乏增强了坏死细胞启动的DC对已建立的肿瘤的抗肿瘤免疫反应的能力。我们的发现定义了我们认为的一种新机制，即MFG-E8通过调节死亡细胞的识别模式来调节DC的免疫原性。控制DC中MFG-E8的水平可能成为控制包括癌症和自身免疫在内的各种病理条件引起的炎性微环境的有用策略。
Dendritic cells (DC) manipulate tissue homeostasis by recognizing dying cells and controlling immune functions. However, the precise mechanisms by which DC recognize different types of dying cells and devise distinct immunologic consequences remain largely obscure. Herein, we demonstrate that Milk-fat globule-EGF VIII (MFG-E8) is a critical mediator controlling DC immunogenicity in inflammatory microenvironments. MFG-E8 restrains DC-mediated uptake and recognition of necrotic cells. The MFG-E8-mediated suppression of necrotic cell uptake by DC resulted in the decreased proinflammatory cytokines production and activated signal components such as STAT3 and A20, which are critical to maintain tolerogenic properties of DC. Furthermore, the DC-derived MFG-E8 negatively regulates the cross-priming and effector functions of antigen-specific T cells upon recognition of necrotic cells. MFG-E8 deficiency enhances an ability of necrotic cell-primed DC to stimulate antitumor immune responses against established tumors. Our findings define what we believe to a novel mechanism whereby MFG-E8 regulates the immunogenicity of DC by modulating the modes of recognition of dying cells. Manipulating MFG-E8 levels in DC may serve as a useful strategy for controlling inflammatory microenvironments caused by various pathological conditions including cancer and autoimmunity.
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