Carbohydrate Oxidation Acidifies Endosomes, Regulating Antigen Processing and TLR9 Signaling
Carbohydrate Oxidation Acidifies Endosomes, Regulating Antigen Processing and TLR9 Signaling
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DOI：
10.4049/jimmunol.0903168
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Cobb, Brian A.
中科院分区：
文献类型：
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作者：
Lewis, Colleen J.;Cobb, Brian A.
吞噬细胞通过表面碳水化合物的氧化裂解杀死被包裹的微生物，释放聚糖片段和微生物内容物，这些内容物作为免疫受体的配体，为免疫受体量身定制针对攻击病原体的免疫反应。多糖片段作为MHC II类（MHC II）配体和先天受体激动剂，而微生物蛋白作为蛋白水解裂解和MHC II呈递的底物，释放的核酸激活先天模式识别受体（如TLR9）。在目前的研究中，活的巨噬细胞和树突状细胞的共聚焦显微镜显示，碳水化合物的内吞作用导致囊泡酸化独立于质子泵活性。在摄入碳水化合物的情况下，酸化依赖于no介导的氧化，足以负调控T细胞依赖性多糖Ag的裂解，促进酸依赖性蛋白Ag的加工，并促进cpg介导的TLR9信号传导。我们的研究结果导致了一个模型，在这个模型中，包裹微生物的碳水化合物氧化通过促进MHC ii介导的Ag加工以及通过TLR9信号传导对释放的微生物DNA的先天反应，促进了针对微生物蛋白质和碳水化合物Ags的适应性免疫反应。中华免疫学杂志，2010,18(4):389 -3800。
Phagocytes kill encapsulated microbes through oxidative cleavage of surface carbohydrates, releasing glycan fragments and microbial contents that serve as ligands for immune receptors, which tailor the immune response against the offending pathogen. The glycan fragments serve as MHC class II (MHC II) ligands and innate receptor agonists, whereas microbial proteins serve as substrates for proteolytic cleavage and MHC II presentation, and released nucleic acids activate innate pattern-recognition receptors (e.g., TLR9). In the current study, confocal microscopy of live macrophages and dendritic cells revealed that endocytosis of carbohydrates lead to vesicular acidification independent of proton pump activity. Acidification was dependent on NO-mediated oxidation in the presence of the ingested carbohydrate and was sufficient to negatively regulate T cell-dependent polysaccharide Ag cleavage, promote acid-dependent protein Ag processing, and facilitate CpG-mediated TLR9 signaling. Our findings lead to a model in which oxidation of carbohydrates from encapsulated microbes facilitates adaptive immune responses against microbial protein and carbohydrate Ags through promoting Ag processing for MHC II-mediated presentation as well as innate responses against released microbial DNA via TLR9 signaling. The Journal of Immunology, 2010,184: 3789-3800.