The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis.
The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis.
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DOI：
10.4049/jimmunol.1003478
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发表时间：
2011-12-15
期刊：
影响因子：
--
通讯作者：
Gröne HJ
中科院分区：
文献类型：
--
作者：
Popovic ZV;Wang S;Papatriantafyllou M;Kaya Z;Porubsky S;Meisner M;Bonrouhi M;Burgdorf S;Young MF;Schaefer L;Gröne HJ
双糖链蛋白聚糖是一种普遍存在于包括心脏在内的多种器官的细胞外基质中的蛋白聚糖，据报道在心肌梗塞中过度表达。心肌梗死可能因心包炎而复杂化，但迄今为止机制尚不清楚。我们的目的是研究 TLR2/TLR4 配体双糖链蛋白聚糖增强心肌细胞坏死时释放的特定抗原呈递的能力。在体外，来自 WT (C57BL/6)、TLR2、TLR4、MyD88 或 TRIF 缺陷小鼠的 Ova 脉冲骨髓来源的树突状细胞与 LPS、双糖链蛋白聚糖或载体共同处理，并与 Ova 识别 MHCI 或 MHCII 限制性 T 细胞一起孵育。 Biglycan 以 TLR2 和 TLR4 途径依赖的方式将 Ova 特异性交叉引发与 MHCI 限制性 T 细胞增强了 80% 以上。因此，MyD88 和 TRIF 缺陷的 DC 所引起的双糖链蛋白聚糖诱导的交叉引发被强烈减弱。 MHCII 限制性 T 细胞的 Ova 特异性激活主要依赖于 TLR4。我们的第一个体内关联是由注射心脏银脉冲 DC (BALB/c) 引发的实验性自身免疫性心包炎模型。双糖链蛋白聚糖处理的 DC 引发心包炎的程度和强度与 LPS 处理的 DC 相当（平均分分别为 1.3±0.3 和 1.5±0.4）。用 TLR4 缺陷的 DC 替代消除了这种效应。在第二种体内方法中，在诱导心肌梗塞后两周对野生型和双糖链蛋白聚糖缺陷型小鼠进行随访。与双聚糖缺陷动物相比，WT 小鼠表现出显着更高的心肌 T 淋巴细胞浸润。我们得出结论，TLR2/4 配体双糖链蛋白聚糖（心肌基质的一个组成部分）可能通过 MyD88 和 TRIF 增强 Ag 特异性 T 细胞启动，并刺激自身免疫性心包炎。
Biglycan is a proteoglycan ubiquitously present in extracellular matrix of a variety of organs including heart and has been reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through to date unclear mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific Ags released upon cardiomyocyte necrosis. In vitro, Ova-pulsed bone-marrow derived dendritic cells from WT (C57BL/6), TLR2-, TLR4-, MyD88- or TRIF- deficient mice were co-treated with LPS, biglycan or vehicle and incubated with Ova-recognizing MHCI- or MHCII-restricted T cells. Biglycan enhanced Ova-specific cross-priming by more than 80% to MHCI-restricted T cells in both TLR2 - and TLR4 – pathway dependent manner. Accordingly, biglycan-induced cross-priming by both MyD88- and TRIF-deficient DCs was strongly diminished. Ova-specific activation of MHCII-restricted T cells was predominantly TLR4-dependent. Our first in vivo correlate was a model of experimental autoimmune perimyocarditis triggered by injection of cardiac-Ag pulsed DCs (BALB/c). Biglycan-treated DCs triggered perimyocarditis in extent and intensity comparable to LPS-treated DCs (average scores 1.3±0.3 and 1.5±0.4, respectively). Substitution with TLR4-deficient DCs abolished this effect. In a second in vivo approach, WT and biglycan-deficient mice were followed two weeks after induction of myocardial infarction. WT mice demonstrated significantly higher myocardial T-lymphocyte infiltration in comparison to biglycan-deficient animals. We conclude that TLR2/4 ligand biglycan, a component of the myocardial matrix, may enhance Ag-specific T cell priming via MyD88 and TRIF and stimulate autoimmune perimyocarditis.
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影响因子：
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