Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity.
Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity.
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皮肤引流淋巴结中树突状细胞亚群比例的改变会促进 Th2 驱动的接触性超敏反应。
DOI：
10.1073/pnas.2021364118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Colonna,Marco
中科院分区：
文献类型：
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作者：
Miller,HannahL;Andhey,PrabhakarSairam;Swiecki,MelissaK;Rosa,BruceA;Zaitsev,Konstantin;Villani,Alexandra-Chloe;Mitreva,Makedonka;Artyomov,MaximN;Gilfillan,Susan;Cella,Marina;Colonna,Marco
浆细胞样树突状细胞（pDC）专门产生I型IFN（IFN-I）。可通过在小鼠中注射白喉毒素（DT）在体内耗尽pDC，其中pDC表达由人CLEC 4C启动子驱动的白喉毒素受体（DTR）转基因。该启动子富含TCF 4的结合位点，TCF 4是一种促进pDC分化和pDC标志物（包括CLEC 4C）表达的转录因子。在此，我们发现在CLEC 4C-DTR+小鼠中注射DT显著增强了由半抗原异硫氰酸荧光素诱导的接触性超敏反应（CHS）模型中的Th 2依赖性皮肤炎症。出乎意料的是，这种偏向的Th 2应答不依赖于伴随pDC消耗的IFN-I减少。事实上，DT治疗改变了CHS致敏期皮肤引流淋巴结中传统树突状细胞（cDC）的表达; Th 1启动的CD 326 + CD 103 + cDC 1较少，Th 2启动的CD 11b + cDC 2较多。CLEC 4C-DTR + cDC的单细胞RNA测序显示，与pDC一样，CD 326 + DC表达DTR，并且通过DT处理与pDC一起被耗尽。由于CD 326 + DC不表达Tcf 4，DTR表达可能是由尚未确定的转录因子激活CLEC 4C启动子驱动的。这些结果表明，在对过敏原致敏期间，皮肤引流淋巴结中DC表达的改变可引起Th 2驱动的CHS。
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 expressTcf4, 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.