Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1.
Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1.
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DOI：
10.4049/jimmunol.1501239
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Tarbell KV
中科院分区：
文献类型：
--
作者：
Rahman MJ;Rahir G;Dong MB;Zhao Y;Rodrigues KB;Hotta-Iwamura C;Chen Y;Guerrero A;Tarbell KV
先天免疫信号有助于打破自我耐受性，从而引发自身免疫性疾病，如1型糖尿病，但先天免疫信号对随后疾病进展的调节作用尚不清楚。大多数研究都测量了GM-CSF树突状细胞（DC）的体外先天反应，这些细胞在功能上与传统DC （cdc）不同，并且不反映体内DC亚群。为了确定自身免疫性NOD小鼠是否有1型IFN先天反应性的改变，我们比较了在体内用TLR9配体CpG（一种强1型IFN诱导剂）刺激的糖尿病前期NOD小鼠和对照C57BL/6 （B6）小鼠的cDCs。在CpG的作用下，NOD小鼠产生更多的1型IFN，表达更高水平的CD40， NOD单核细胞dc产生更多的TNF。然而，在NOD cdc中，cpg诱导的总体转录反应是沉默的。与此相关的是，协同刺激蛋白CD80/CD86（调节性T细胞稳态所需的信号）在NOD cdc上的上调较少。有趣的是，与B6 Rag1 - / -相比，NOD Rag1 - / -小鼠在cpg诱导的CD86上调中也表现出缺陷，这表明这种特殊的先天改变先于适应性自身免疫。NOD dc的反应受损可能发生在IFN-α/β受体下游，因为当加入抗IFN-α/β受体Ab时，NOD和B6小鼠的dc显示出相似的cpg诱导的CD86水平。在NOD CD11c+细胞中，IFN-α -诱导的活化STAT1的核定位明显减少，这与较低的1型IFN反应性一致。总之，NOD dc表现出先天反应的改变，其特征是1型IFN增强和单核细胞来源dc的激活，但cDC 1型IFN反应减弱。
Innate immune signals help break self-tolerance to initiate autoimmune diseases such as type 1 diabetes, but innate contributions to subsequent regulation of disease progression are less clear. Most studies have measured in vitro innate responses of GM-CSF dendritic cells (DCs) that are functionally distinct from conventional DCs (cDCs) and do not reflect in vivo DC subsets. To determine whether autoimmune NOD mice have alterations in type 1 IFN innate responsiveness, we compared cDCs from prediabetic NOD and control C57BL/6 (B6) mice stimulated in vivo with the TLR9 ligand CpG, a strong type 1 IFN inducer. In response to CpG, NOD mice produce more type 1 IFN and express higher levels of CD40, and NOD monocyte DCs make more TNF. However, the overall CpG-induced transcriptional response is muted in NOD cDCs. Of relevance the costimulatory proteins CD80/CD86, signals needed for regulatory T cell homeostasis, are upregulated less on NOD cDCs. Interestingly, NOD Rag1−/− mice also display a defect in CpG-induced CD86 upregulation compared with B6 Rag1−/−, indicating this particular innate alteration precedes adaptive autoimmunity. The impaired response in NOD DCs is likely downstream of the IFN-α/β receptor because DCs from NOD and B6 mice show similar CpG-induced CD86 levels when anti–IFN-α/β receptor Ab is added. IFN-α–induced nuclear localization of activated STAT1 is markedly reduced in NOD CD11c+ cells, consistent with lower type 1 IFN responsiveness. In conclusion, NOD DCs display altered innate responses characterized by enhanced type 1 IFN and activation of monocyte-derived DCs but diminished cDC type 1 IFN response.
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