Endotoxin can induce MyD88-deficient dendritic cells to support Th2 cell differentiation
Endotoxin can induce MyD88-deficient dendritic cells to support Th2 cell differentiation
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DOI：
10.1093/intimm/dxf039
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Akira, S
中科院分区：
文献类型：
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作者：
Kaisho, T;Hoshino, K;Akira, S
Toll样受体(Toll-like Receptor，TLR)信号激活树突状细胞(DC)分泌促炎细胞因子，上调共刺激分子的表达，从而将先天免疫和获得性免疫联系起来。TLR相关的接头蛋白MyD88对于TLR诱导的细胞因子的产生是必不可少的。然而，在TLR4配体的作用下，MyD88缺失的DC(MyD88(-/-))可以上调共刺激分子的表达，增强其T细胞刺激活性，表明通过TLR4的MyD88非依赖途径可以诱导DC成熟的某些特征。在本研究中，我们进一步研究了内毒素刺激的MyD88(-/-)DC的功能。野生型DC作为对内毒素的应答，可增强其诱导异基因混合淋巴细胞反应产生干扰素-γ的能力。相反，在对内毒素的反应中，MyD88(-/-)DC增强了它们诱导IL-4而不是干扰素-γ的能力。在MyD88(-/-)DC中T(H)1诱导的细胞因子的产生减少并不能完全解释其T(H)2细胞支持能力的增强，因为DC中缺乏T(H)1诱导的细胞因子会导致干扰素-γ的损伤，但不会导致异基因MLR中IL-4的产生增加。用佐剂进行的体内实验也显示了MyD88(-/-)小鼠的T(H)2偏斜免疫反应。这些结果表明，通过TLR4的MyD88非依赖通路可以赋予DC支持T(H)2免疫应答的能力。
Toll-like receptor (TLR) signaling activates dendritic cells (DC) to secrete proinflammatory cytokines and up-regulate co-stimulatory molecule expression, thereby linking innate and adaptive immunity. A TLR-associated adapter protein, MyD88, is essential for cytokine production induced by TLR. However, in response to a TLR4 ligand, lipopolysaccharide (LPS), MyD88-deficient (MyD88(-/-)) DC can up-regulate co-stimulatory molecule expression and enhance their T cell stimulatory activity, indicating that the MyD88-independent pathway through TLR4 can induce some features of DC maturation. In this study, we have further characterized function of LPS-stimulated, MyD88(-/-) DC. In response to LPS, wild-type DC could enhance their ability to induce IFN-gamma production in allogeneic mixed lymphocyte reaction (alloMLR). In contrast, in response to LPS, MyD88(-/-) DC augmented their ability to induce IL-4 instead of IFN-gamma in alloMLR. Impaired production of T(h)1-inducing cytokines in MyD88(-/-) DC cannot fully account for their increased T(h)2 cell-supporting ability, because absence of T(h)1-inducing cytokines in DC caused impairment of IFN-gamma, but did not lead to augmentation of IL-4 production in alloMLR. In vivo experiments with adjuvants also revealed T(h)2-skewed immune responses in MyD88(-/-) mice. These results demonstrate that the MyD88-independent pathway through TLR4 can confer on DC the ability to support T(h)2 immune responses.