Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12
Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12
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DOI：
10.4049/jimmunol.180.9.6000
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Moyle, Matthew
中科院分区：
文献类型：
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作者：
Lamhamedi-Cherradi, Salah-Eddine;Martin, Rachel Elizabeth;Moyle, Matthew
过敏原能够在由树突状细胞（DC）介导的过程中使T细胞免疫应答朝向Th 2细胞因子谱极化。来源于曲霉属物种的蛋白酶（曲霉蛋白酶; AP）已经显示，当在过敏性气道疾病模型中在远离肺的部位直接施用至气道并且没有佐剂或预先引发免疫时，诱导Th 2样免疫应答。为了探索Th 2免疫应答的机制，我们研究了AP对DC功能的影响。我们发现，来自健康供体的CD 14（+）单核细胞的人DC在与AP孵育时经历部分成熟。与用LPS活化的DC致敏的幼稚T细胞相比，用AP活化的DC致敏的幼稚同种异体T细胞增殖并显示IL-4的产生增强和IFN-γ的表达降低。DC的全局基因表达分析显示，与LPS激活的DC相比，AP激活的DC中IL-12 p40的表达相对较低，并且通过ELISA在蛋白水平证实了这一点。当用AP激活DC时，将外源性IL-12 p70加入DC和T细胞的共培养物中导致IL-4表达减少和IFN-γ表达增加。当AP的蛋白水解活性被化学失活中和时，它不能上调DC上的共刺激分子，并且这些DC不能引发幼稚T细胞中的Th 2应答。这些发现提供了一种机制，解释如何蛋白水解活性过敏原可以优先诱导Th 2反应，通过有限的成熟DO与IL-12的生产减少。
Allergens are capable of polarizing the T cell immune response toward a Th2 cytokine profile in a process that is mediated by dendritic cells (DCs). Proteases derived from Aspergillus species (Aspergillus proteases; AP) have been shown to induce a Th2-like immune response when administered directly to the airway and without adjuvant or prior priming immunizations at sites remote from the lung in models of allergic airway disease. To explore mechanisms that underlie the Th2 immune response, we have investigated the effect of AP on DC function. We found that human DCs derived from CD14(+) monocytes from healthy donors underwent partial maturation when incubated with AP. Naive allogeneic T cells primed with AP-activated DCs proliferated and displayed enhanced production of IL-4 and reduced expression of IFN-gamma as compared with naive T cells primed with LPS-activated DCs. Global gene expression analysis of DCs revealed relatively low expression of IL-12p40 in AP-activated DCs as compared with those activated by LPS, and this was confirmed at the protein level by ELISA. Exogenous IL-12p70 added to cocultures of DCs and T cells resulted in reduced IL-4 and increased IFN-gamma expression when DCs were activated with AP. When the proteolytic activity of AP was neutralized by chemical inactivation it failed to up-regulate costimulatory molecules on DCs, and these DCs did not prime a Th2 response in naive T cells. These findings provide a mechanism for explaining how proteolytically active allergens could preferentially induce Th2 responses through limited maturation of DO with reduced production of IL-12.