Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization
Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization
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DOI：
10.4049/jimmunol.1100203
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发表时间：
2011-06
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通讯作者：
B. Pérez‐Cabezas;M. Naranjo-Gómez;P. Bastos-Amador;Gerard Requena-Fernández;R. Pujol-Borrell;F. Borràs
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作者：
B. Pérez‐Cabezas;M. Naranjo-Gómez;P. Bastos-Amador;Gerard Requena-Fernández;R. Pujol-Borrell;F. Borràs
Notch信号参与多种细胞过程。最近的数据也支持Notch信号在免疫应答调节中的突出作用。在这项研究中，我们分析了Notch受体和配体在人血液常规树突状细胞（cdc）和浆细胞样树突状细胞（pDCs）上的表达和功能。Notch分子对TLR激活的表达和调节在cdc和pDCs之间存在部分差异，但DAPT的特异性抑制清楚地揭示了Notch通路在两种细胞类型中的功能参与。除了诱导Notch靶基因和调节成熟标记外，Notch通路还参与DC亚群分泌一些特定细胞因子/趋化因子的差异。Notch连接诱导cDCs分泌IL-10和CCL19，而Notch抑制导致这些蛋白的产生减少。对于pDCs， Notch激活可诱导TNF-α，而Notch抑制可显著抑制CCL19、CXCL9、CXCL10和TNF-α的分泌。此外，DC亚群的Notch调节差异影响同种异体刺激T细胞的极化。我们的研究结果表明Notch通路可能是控制人类DC反应的另一种机制，对cdc和pDCs具有不同的活性。这种控制机制可能最终有助于确定这些细胞在免疫反应的特定条件下促进的局部环境。
Notch signaling is involved in multiple cellular processes. Recent data also support the prominent role of Notch signaling in the regulation of the immune response. In this study, we analyzed the expression and function of Notch receptors and ligands on both human blood conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). The expression and modulation upon TLR activation of Notch molecules partially differed between cDCs and pDCs, but functional involvement of the Notch pathway in both cell types was clearly revealed by specific inhibition using DAPT. Beyond the induction of Notch target genes and modulation of maturation markers, Notch pathway was also involved in a differential secretion of some specific cytokines/chemokines by DC subsets. Whereas Notch ligation induced IL-10 and CCL19 secretion in cDCs, Notch inhibition resulted in a diminished production of these proteins. With regard to pDCs, Notch activation induced TNF-α whereas Notch inhibition significantly abrogated the secretion of CCL19, CXCL9, CXCL10, and TNF-α. Additionally, Notch modulation of DC subsets differentially affected Th polarization of allostimulated T cells. Our results suggest that the Notch pathway may function as an additional mechanism controlling human DC responses, with differential activity on cDCs and pDCs. This control mechanism may ultimately contribute to define the local milieu promoted by these cells under the particular conditions of the immune response.