Aspergillus fumigatus-Induced IL-22 Is Not Restricted to a Specific Th Cell Subset and Is Dependent on Complement Receptor 3
Aspergillus fumigatus-Induced IL-22 Is Not Restricted to a Specific Th Cell Subset and Is Dependent on Complement Receptor 3
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DOI：
10.4049/jimmunol.1202601
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发表时间：
2013-06-01
影响因子：
4.4
通讯作者：
van de Veerdonk, Frank L.
中科院分区：
文献类型：
--
作者：
Gresnigt, Mark S.;Becker, Katharina L.;van de Veerdonk, Frank L.
烟曲霉诱导的 Th 细胞反应已在小鼠模型中得到广泛研究。然而，烟曲霉诱导的人类 Th 细胞亚群的分化要求和特征仍然不明确。我们证明烟曲霉在人类 PBMC 中诱导 Th1 和 Th17 亚群。此外，我们发现与 IL-17A 相比，细胞因子 IL-22 并不局限于特定的 Th 子集。扭曲这些曲霉诱导的 Th 细胞反应的模式识别和细胞因子途径是 TLR4 和 IL-1、IL-23 和 TNF-α 依赖性的。这些途径对于细胞因子 IL-17A 和 IL-22 的产生特别重要。此外，我们的数据表明，dectin-1/Syk 途径是多余的，并且 TLR2 对曲霉菌诱导的 IL-17A 和 IL-22 产生具有抑制作用。值得注意的是，阻断补体受体 (CR)3 显着降低曲霉菌诱导的 Th1 和 Th17 反应，并且这与补体系统的激活无关。 CR3 是已知的 β-1,3-葡聚糖受体；然而，阻断 CR3 对热灭活的曲霉分生孢子诱导的 Th 细胞反应有显着影响，而曲霉分生孢子的细胞表面的 β-葡聚糖表达量极少。总的来说，这些数据表征了曲霉属诱导的人类 Th 细胞亚群，证明产生 IL-22 的能力并不限于特定的 T 细胞亚群，并提供证据表明 CR3 可能在宿主对曲霉属的适应性防御中发挥重要作用，尽管配体及其作用仍有待阐明。
Th cell responses induced by Aspergillus fumigatus have been extensively investigated in mouse models. However, the requirements for differentiation and the characteristics of A. fumigatus induced human Th cell subsets remain poorly defined. We demonstrate that A. fumigatus induces Th1 and Th17 subsets in human PBMCs. Moreover, we show that the cytokine IL-22 is not restricted to a specific Th subset, in contrast to IL-17A. The pattern recognition and cytokine pathways that skew these Aspergillus-induced Th cell responses are TLR4- and IL-1, IL-23, and TNF-alpha dependent. These pathways are of specific importance for production of the cytokines IL-17A and IL-22. Additionally, our data reveal that the dectin-1/Syk pathway is redundant and that TLR2 has an inhibitory effect on Aspergillus-induced IL-17A and IL-22 production. Notably, blocking complement receptor (CR)3 significantly reduced Aspergillus-induced Th1 and Th17 responses, and this was independent on the activation of the complement system. CR3 is a known receptor for beta-1,3-glucan; however, blocking CR3 had significant effects on Th cell responses induced by heat-killed Aspergillus conidia, which have minimal beta-glucan expression on their cell surface. Collectively, these data characterize the human Th cell subsets induced by Aspergillus, demonstrate that the capability to produce IL-22 is not restricted to a specific T cell subset, and provide evidence that CR3 might play a significant role in the adaptive host defense against Aspergillus, although the ligand and its action remain to be elucidated.