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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Presensitizing with a Toll-like receptor 3 ligand impairs CD8 T-cell effector differentiation and IL-33 responsiveness
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Presensitizing with a Toll-like receptor 3 ligand impairs CD8 T-cell effector differentiation and IL-33 responsiveness

机译:用Toll样受体3配体预敏化会损害CD8 T细胞效应子分化和IL-33反应性

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摘要

The synthetic double-stranded RNA poly(l:C) is commonly used as an adjuvant to boost CD8 T-cell function; however, polyinosinic: polycytidylic acid [poly(l:C)] can also suppress autoimmune disease. The mechanism by which a single adjuvant achieves two distinct immunoregulatory roles is unknown. Although it is clear that co-administration of poly(l:C) with antigen elicits strong adjuvant effects in mice, we found that poly(l:C) injection before antigen substantially reduced antigen-dependent CD8 T-cell responses. Notably, CD8 T cells sensitized in poly(l:C)-pretreated mice failed to fully up-regulate IL-33R (ST2), which led to impaired T-cell receptor-independent responses to IL-33. In contrast, nonsensitized effector CD8 T cells responded robustly to IL-33 using a two-signal cytokine mechanism. During an acute lung response to Staphylococcus aureus enterotoxin, peripheral injection of poly(l:C) manifested a suppressive process by inhibiting the differentiation of both antigen- and IL-33-responsive CD8 effectors systemically. These findings highlight that early exposure to double-stranded RNA reverses its role as an adjuvant and, importantly, prevents IL-33R up-regu-lation on CD8 effector T cells to dampen inflammation.
机译:合成的双链RNA poly(1:C)通常用作佐剂,以增强CD8 T细胞功能。但是,多肌苷酸:聚胞苷酸[poly(l:C)]也可以抑制自身免疫性疾病。单一佐剂达到两种不同的免疫调节作用的机制尚不清楚。尽管很明显,将聚(1:C)与抗原共同给药会在小鼠中产生强烈的佐剂作用,但我们发现在抗原前进行聚(1:C)注射可大大降低抗原依赖性CD8 T细胞反应。值得注意的是,在经过poly(1:C)预处理的小鼠中敏化的CD8 T细胞未能完全上调IL-33R(ST2),从而导致对IL-33的T细胞受体非依赖性应答受损。相比之下,未敏化的效应CD8 T细胞使用两个信号的细胞因子机制对IL-33产生强烈反应。在对金黄色葡萄球菌肠毒素的急性肺反应中,聚(1:C)的外周注射通过全身抑制抗原和IL-33响应CD8效应子的分化而表现出抑制过程。这些发现突出表明,早期暴露于双链RNA会逆转其作为佐剂的作用,并且重要的是,防止IL-33R在CD8效应T细胞上的上调抑制炎症。

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