The Transcription Factor E74-like Factor 4 Suppresses Differentiation of Proliferating CD4+ T Cells to the Th17 Lineage
The Transcription Factor E74-like Factor 4 Suppresses Differentiation of Proliferating CD4+ T Cells to the Th17 Lineage
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DOI：
10.4049/jimmunol.1301372
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发表时间：
2014-01-01
影响因子：
4.4
通讯作者：
Lacorazza, H. Daniel
中科院分区：
文献类型：
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作者：
Lee, Ping-Hsien;Puppi, Monica;Lacorazza, H. Daniel
CD4(+) T细胞分化为不同的T细胞谱系是由启动位点的细胞因子环境和潜在的转录回路驱动的。尽管已经确定了许多正调节因子，但尚不清楚如何在转录水平上抑制这一过程。在这项研究中，我们报道了e - 26 （ETS）转录因子e74样因子4 （ELF4）在体外和体内抑制Th17细胞的分化。在IL-6和tgf - β（或IL-6、IL-23和IL-1 β）存在下培养幼稚的Elf4 2/2 CD4(+) T细胞，与野生型对照相比，il - 17a阳性细胞数量增加。相反，向Th1、Th2或调节性T细胞的分化在很大程度上不受ELF4缺失的影响。在Elf4(-/-) CD4(+) T细胞中观察到参与Th17分化的基因表达增加，这表明Elf4控制了它们进入Th17谱系的编程，而不仅仅是IL-17A基因的表达。尽管初始CD4(+) T细胞正常增殖，但ELF4的缺失降低了每次细胞分裂中诱导IL-17A所需的IL-6和tgf - β信号。ELF4不像另一个ETS转录因子ETS1那样通过促进IL-2的产生来抑制Th17的分化。Elf4（-/-）小鼠在稳态时固有层中Th17细胞数量增加，免疫后淋巴结中Th17细胞数量增加，最重要的是，实验性自身免疫性脑脊髓炎诱导后中枢神经系统中Th17细胞数量增加，导致疾病严重程度增加。总的来说，我们的研究结果表明，ELF4通过调节Th17分化程序的承诺来抑制CD4(+) T细胞分裂中的Th17分化。
The differentiation of CD4(+) T cells into different Th lineages is driven by cytokine milieu in the priming site and the underlying transcriptional circuitry. Even though many positive regulators have been identified, it is not clear how this process is inhibited at transcriptional level. In this study, we report that the E-twenty six (ETS) transcription factor E74-like factor 4 (ELF4) suppresses the differentiation of Th17 cells both in vitro and in vivo. Culture of naive Elf4 2/2 CD4(+) T cells in the presence of IL-6 and TGF-beta (or IL-6, IL-23, and IL-1 beta) resulted in increased numbers of IL-17A-positive cells compared with wild-type controls. In contrast, the differentiation to Th1, Th2, or regulatory T cells was largely unaffected by loss of ELF4. The increased expression of genes involved in Th17 differentiation observed in Elf4(-/-) CD4(+) T cells suggested that ELF4 controls their programming into the Th17 lineage rather than only IL-17A gene expression. Despite normal proliferation of naive CD4(+) T cells, loss of ELF4 lowered the requirement of IL-6 and TGF-beta signaling for IL-17A induction in each cell division. ELF4 did not inhibit Th17 differentiation by promoting IL-2 production as proposed for another ETS transcription factor, ETS1. Elf4(-/-) mice showed increased numbers of Th17 cells in the lamina propria at steady state, in lymph nodes after immunization, and, most importantly, in the CNS following experimental autoimmune encephalomyelitis induction, contributing to the increased disease severity. Collectively, our findings suggest that ELF4 restrains Th17 differentiation in dividing CD4(+) T cells by regulating commitment to the Th17 differentiation program.