IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation.
IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation.
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DOI：
10.1084/jem.20150568
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发表时间：
2016-02-08
期刊：
影响因子：
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通讯作者：
Edelson BT
中科院分区：
文献类型：
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作者：
Lin CC;Bradstreet TR;Schwarzkopf EA;Jarjour NN;Chou C;Archambault AS;Sim J;Zinselmeyer BH;Carrero JA;Wu GF;Taneja R;Artyomov MN;Russell JH;Edelson BT
Lin等表明，Bhlhe 40表达鉴定致脑炎性CD 4 + T辅助细胞，并确定在实验性自身免疫性脑脊髓炎（多发性硬化症的小鼠模型）中有活性的百日咳毒素-IL-1-Bhlhe 40途径。定义自身反应性T辅助细胞（Th）致病性的特征仍然不清楚。我们以前已经表明，Th细胞需要转录因子Bhlhe 40介导实验性自身免疫性脑脊髓炎（EAE），多发性硬化症的小鼠模型。在此，使用Bhlhe 40报告小鼠并分析多克隆和TCR转基因Th细胞，我们发现在EAE诱导后Bhlhe 40表达是异质的，其中Bhlhe 40表达细胞显示IFN-γ、IL-17 A和粒细胞-巨噬细胞集落刺激因子的显著产生。在过继转移EAE模型中，Bhlhe 40缺陷型Th 1和Th 17细胞均为非致脑炎性。百日咳毒素（PTX）是主动诱导EAE的经典共佐剂，其促进引流淋巴结中髓样细胞产生IL-1β，并作为Th细胞中Bhlhe 40表达的强刺激物。此外，PTX共佐剂性是Bhlhe 40依赖性的。IL-1β诱导极化Th 17细胞中的Bhlhe 40表达，并且表达Bhlhe 40的细胞表现出致脑炎的转录特征。在体内，IL-1 R信号传导是免疫后Th细胞完全表达Bhlhe 40所必需的。总之，我们证明Bhlhe 40表达鉴定致脑炎性Th细胞，并定义了在EAE中有活性的PTX-IL-1-Bhlhe 40通路。
Lin et al. show that Bhlhe40 expression identifies encephalitogenic CD4+ T helper cells and define a pertussis toxin–IL-1–Bhlhe40 pathway active in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The features that define autoreactive T helper (Th) cell pathogenicity remain obscure. We have previously shown that Th cells require the transcription factor Bhlhe40 to mediate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here, using Bhlhe40 reporter mice and analyzing both polyclonal and TCR transgenic Th cells, we found that Bhlhe40 expression was heterogeneous after EAE induction, with Bhlhe40-expressing cells displaying marked production of IFN-γ, IL-17A, and granulocyte-macrophage colony-stimulating factor. In adoptive transfer EAE models, Bhlhe40-deficient Th1 and Th17 cells were both nonencephalitogenic. Pertussis toxin (PTX), a classical co-adjuvant for actively induced EAE, promoted IL-1β production by myeloid cells in the draining lymph node and served as a strong stimulus for Bhlhe40 expression in Th cells. Furthermore, PTX co-adjuvanticity was Bhlhe40 dependent. IL-1β induced Bhlhe40 expression in polarized Th17 cells, and Bhlhe40-expressing cells exhibited an encephalitogenic transcriptional signature. In vivo, IL-1R signaling was required for full Bhlhe40 expression by Th cells after immunization. Overall, we demonstrate that Bhlhe40 expression identifies encephalitogenic Th cells and defines a PTX–IL-1–Bhlhe40 pathway active in EAE.