Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-01-19 , DOI: 10.1073/pnas.2021364118 Hannah L Miller 1 , Prabhakar Sairam Andhey 1 , Melissa K Swiecki 2 , Bruce A Rosa 3, 4 , Konstantin Zaitsev 1, 5 , Alexandra-Chloe Villani 6 , Makedonka Mitreva 3, 4 , Maxim N Artyomov 1 , Susan Gilfillan 1 , Marina Cella 1 , Marco Colonna 7
Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+ mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+ CD103+ cDC1 and more Th2-priming CD11b+ cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+ cDCs revealed that CD326+ DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+ DCs did not express Tcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.
中文翻译:
皮肤引流淋巴结中树突状细胞亚群比例的改变促进 Th2 驱动的接触超敏反应 [免疫学和炎症]
浆细胞样树突状细胞 (pDC) 专门生产 I 型干扰素 (IFN-I)。pDCs 可以通过在小鼠体内注射白喉毒素 (DT) 来消耗,其中 pDCs 表达由人类 CLEC4C 启动子驱动的白喉毒素受体 (DTR) 转基因。该启动子富含 TCF4 的结合位点,TCF4 是一种促进 pDC 分化和 pDC 标记(包括 CLEC4C)表达的转录因子。在这里,我们发现在 CLEC4C-DTR +中注入 DT小鼠在由半抗原异硫氰酸荧光素诱导的接触超敏反应 (CHS) 模型中显着增加了 Th2 依赖性皮肤炎症。出乎意料的是,这种有偏见的 Th2 反应独立于伴随 pDC 耗竭的 IFN-I 减少。事实上,DT 治疗改变了 CHS 致敏阶段皮肤引流淋巴结中常规树突状细胞 (cDC) 的表现。Th1 引发的 CD326 + CD103 + cDC1 较少,而 Th2 引发的 CD11b + cDC2 则较多。CLEC4C-DTR + cDCs 的单细胞 RNA 测序显示,CD326 + DCs 与 pDCs 一样,表达 DTR 并通过 DT 处理与 pDCs 一起耗尽。由于 CD326 + DCs 不表达Tcf4、DTR 表达可能由激活 CLEC4C 启动子的尚未确定的转录因子驱动。这些结果表明,在对过敏原敏感期间皮肤引流淋巴结中 DC 表现的改变可导致 Th2 驱动的 CHS。