Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens.
Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens.
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DOI：
10.1172/jci43254
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
YuFeng Peng;K. Elkon
中科院分区：
文献类型：
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作者：
YuFeng Peng;K. Elkon
凋亡细胞必须被迅速清除，因为这个过程中的缺陷可能导致自身免疫。乳脂球 EGF 因子 8 (MFG-E8) 与凋亡细胞结合，并通过与吞噬细胞相互作用促进其清除。 MFG-E8 缺陷的小鼠会出现与体内凋亡细胞积聚相关的狼疮样自身免疫。在这里，我们证明 MFG-E8 控制细胞碎片的吞噬摄取以及它们在细胞内加工成 MHC-抗原复合物。老年 Mfge8-/- 小鼠自发出现与 CD8+ T 细胞浸润和效应记忆 CD8+ T 细胞显着激活相关的皮炎。 Mfge8-/- 小鼠中 CD8+ T 细胞对外源性和内源性凋亡细胞相关抗原的反应均增强。 MFG-E8 缺陷加速了自身免疫性糖尿病小鼠模型的发病。 CD8+ T 细胞反应增强归因于 DC 交叉呈递的增加以及抗原-MHCI 复合物检测的增加。细胞内运输分析显示，野生型 DC 摄取的完整凋亡细胞快速与溶酶体融合，而较小的碎片在 Mfge8-/- DC 内体区室中持续 24 小时。这些观察结果表明，MFG-E8 缺陷不仅通过延迟死亡细胞的清除，而且通过改变细胞内处理，从而增强自身抗原的呈递，从而促进对自身抗原的免疫反应。
Apoptotic cells must be rapidly cleared, as defects in this process can lead to autoimmunity. Milk fat globule EGF factor 8 (MFG-E8) binds to apoptotic cells and facilitates their removal through interaction with phagocytes. Mice deficient in MFG-E8 develop lupus-like autoimmunity associated with accumulation of apoptotic cells in vivo. Here, we have shown that MFG-E8 controls phagocytic ingestion of cell fragments as well as their intracellular processing into MHC-antigen complexes. Older Mfge8-/- mice spontaneously developed dermatitis associated with CD8+ T cell infiltration and striking activation of effector memory CD8+ T cells. CD8+ T cell responses to both exogenous and endogenous apoptotic cell-associated antigens were enhanced in Mfge8-/- mice. MFG-E8 deficiency accelerated the onset of disease in a mouse model of autoimmune diabetes. Enhanced CD8+ T cell responses were attributed to increased cross-presentation by DCs along with increased detection of antigen-MHCI complexes. Intracellular trafficking analysis revealed that intact apoptotic cells ingested by wild-type DCs rapidly fused with lysosomes, whereas smaller fragments persisted in Mfge8-/- DC endosomal compartments for 24 hours. These observations suggest that MFG-E8 deficiency promotes immune responses to self antigens not only by delaying the clearance of dying cells but also by altering intracellular processing, leading to enhanced self-antigen presentation.