Department of Molecular Immunology, IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany; Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
Eur J Immunol. 2014 Feb;44(2):500-10. doi: 10.1002/eji.201343820. Epub 2013 Dec 12.
The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady-state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α⁻CD11b⁺ LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α⁻ and CD8α⁺ splenic DC subsets and enhances cross-presentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b⁺ DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b⁺CCL17⁺ DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.
树突状细胞衍生的趋化因子 CCL17 是 CCR4 的配体，已被证明可促进多种炎症性疾病，如特应性皮炎、动脉粥样硬化和炎症性肠病。在稳态条件下，甚至在全身用 LPS 刺激后，CCL17 也不会在驻留的脾树突状细胞（与 CD8α⁻CD11b⁺LN 树突状细胞相反）中表达，后者在成熟后特别大量产生 CCL17。然而，通过α-半乳糖神经酰胺刺激全身 NKT 细胞激活后，CCL17 可以在 CD8α⁻和 CD8α⁺脾树突状细胞亚群中上调，并增强外源性抗原的交叉呈递。基于全基因组表达谱分析，我们现在表明，脾 CD11b⁺树突状细胞易受 IFN-γ 介导的 CCL17 抑制，而 LN CD11b⁺CCL17⁺树突状细胞下调 IFN-γR，对 IFN-γ 的反应性大大降低。在炎症条件下，特别是在 IFN-γRKO 小鼠中缺乏 IFN-γ 信号传导的情况下，GM-CSF 与 IL-4 协同作用强烈诱导脾树突状细胞中 CCL17 的表达。我们的研究结果表明，局部细胞因子微环境和树突状细胞亚群的差异细胞因子反应性调节淋巴器官特异性免疫反应水平的趋化因子表达。
