S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-α Production by Human Plasmacytoid Dendritic Cells
S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-α Production by Human Plasmacytoid Dendritic Cells
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DOI：
10.4049/jimmunol.1403168
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发表时间：
2016-02-15
影响因子：
4.4
通讯作者：
Weigert, Andreas
中科院分区：
文献类型：
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作者：
Dillmann, Christina;Ringel, Christian;Weigert, Andreas
浆细胞样树突状细胞（pDC）响应于TLR 7/9配体产生大量I型IFN。这传递抗病毒作用，激活其他免疫细胞（NK细胞、常规DC、B和T细胞），并引起强烈炎症反应的诱导和扩增。pDC是各种I型IFN驱动的自身免疫性疾病如系统性红斑狼疮或银屑病的关键参与者，但pDC也参与（抗）肿瘤免疫。鞘脂鞘氨醇-1-磷酸（S1 P）通过五种G蛋白偶联受体（S1 PR 1 -5）发出信号，以调节免疫细胞迁移和激活等活动。本研究表明，S1 P刺激人，初级pDC实质上减少了TLR 7/9激活后，不同类型的CpG寡脱氧核苷酸或蜱传脑炎疫苗，这发生在S1 PR 4依赖的方式IFN-α的生产。在机制上，S1 PR 4活化保留了人pDC特异性抑制性受体Ig样转录物7的表面表达。我们提供了新的信息，即Ig样转录本7在受体介导的TLR 7/9配体的内吞作用后迅速内化，以允许高IFN-α产生。这被S1 PR 4信号传导拮抗，从而减少TLR诱导的IFN-α分泌。在功能水平上，减弱的IFN-α产生未能改变pDC依赖性T细胞活化测定中Ag驱动的T细胞增殖，但将T细胞的细胞因子产生从Th 1（IFN-γ）转变为调节（IL-10）谱。总之，S1 PR 4激动剂阻断人pDC活化，因此可能是限制致病性IFN-α产生的有希望的工具。
Plasmacytoid dendritic cells (pDCs) produce large amounts of type I IFN in response to TLR7/9 ligands. This conveys antiviral effects, activates other immune cells (NK cells, conventional DCs, B, and T cells), and causes the induction and expansion of a strong inflammatory response. pDCs are key players in various type I IFN-driven autoimmune diseases such as systemic lupus erythematosus or psoriasis, but pDCs are also involved in (anti-) tumor immunity. The sphingolipid sphingosine-1-phosphate (S1P) signals through five G-protein-coupled receptors (S1PR1-5) to regulate, among other activities, immune cell migration and activation. The present study shows that S1P stimulation of human, primary pDCs substantially decreases IFN-alpha production after TLR7/9 activation with different types of CpG oligodeoxynucleotides or tick-borne encephalitis vaccine, which occurred in an S1PR4-dependent manner. Mechanistically, S1PR4 activation preserves the surface expression of the human pDC-specific inhibitory receptor Ig-like transcript 7. We provide novel information that Ig-like transcript 7 is rapidly internalized upon receptor-mediated endocytosis of TLR7/9 ligands to allow high IFN-alpha production. This is antagonized by S1PR4 signaling, thus decreasing TLR-induced IFN-alpha secretion. At a functional level, attenuated IFN-alpha production failed to alter Ag-driven T cell proliferation in pDC-dependent T cell activation assays, but shifted cytokine production of T cells from a Th1 (IFN-gamma) to a regulatory (IL-10) profile. In conclusion, S1PR4 agonists block human pDC activation and may therefore be a promising tool to restrict pathogenic IFN-alpha production.