CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells.
CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells.
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DOI：
10.4049/jimmunol.1501658
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发表时间：
2016-02-15
期刊：
影响因子：
--
通讯作者：
Zuniga EI
中科院分区：
文献类型：
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作者：
Macal M;Tam MA;Hesser C;Di Domizio J;Leger P;Gilliet M;Zuniga EI
I 型干扰素 (IFN-I) 是关键的先天介质，可产生深远的抗病毒状态并协调几乎所有免疫细胞的激活。浆细胞样树突状细胞 (pDC) 是最强大的 IFN-I 产生细胞，在病毒感染、癌症和自身免疫性疾病中发挥重要作用。通过比较小鼠 pDC 和传统 (c) DC 的基因表达谱，我们发现 CD28（一种原型 T 细胞刺激受体）在 pDC 中高度表达。引人注目的是，在 Toll 样受体刺激后，CD28 作为 pDC IFN-I 产生的负调节因子，但不影响 pDC 的存活或成熟。重要的是，细胞内在的 CD28 表达在体内 RNA 和 DNA 病毒感染期间抑制了 pDC（和全身性）IFN-I 的产生，从而限制了抗病毒反应并在暴露后早期增强了病毒生长。最后，CD28 还下调皮肤损伤时的 IFN-I 反应。我们的研究发现了一种新的 pDC 调节机制，通过该机制，在大多数表达它的细胞中促进刺激的相同 CD28 分子被共同选择负调节 pDC IFN-I 的产生并限制先天反应。
Type I interferons (IFN-I) are key innate mediators that create a profound antiviral state and orchestrate the activation of almost all immune cells. Plasmacytoid dendritic cells (pDCs) are the most powerful IFN-I producing cells and play important roles during viral infections, cancer, and autoimmune diseases. By comparing gene expression profiles of murine pDCs and conventional (c) DCs we found that CD28, a prototypic T cell stimulatory receptor, was highly expressed in pDCs. Strikingly, CD28 acted as a negative regulator of pDC IFN-I production upon toll-like receptor stimulation but did not affect pDC survival or maturation. Importantly, cell-intrinsic CD28 expression restrained pDC (and systemic) IFN-I production during in vivo RNA and DNA viral infections, limiting antiviral responses and enhancing viral growth early after exposure. Finally, CD28 also down-regulated IFN-I response upon skin injury. Our study identified a new pDC regulatory mechanism by which the same CD28 molecule that promotes stimulation in most cells that express it is co-opted to negatively regulate pDC IFN-I production and limit innate responses.