J Clin Invest. 2014 Jan;124(1):174-87. doi: 10.1172/JCI70103. Epub 2013 Dec 9.
Naive T helper cells differentiate into functionally distinct effector subsets that drive specialized immune responses. Recent studies indicate that some of the effector subsets have plasticity. Here, we used an EAE model and found that Th17 cells deficient in the transcription factor BCL11B upregulated the Th2-associated proteins GATA3 and IL-4 without decreasing RAR-related orphan receptor γ (RORγt), IL-17, and GM-CSF levels. Surprisingly, abnormal IL-4 production affected Th17 cell trafficking, diverting migration from the draining lymph nodes/CNS route to the mesenteric lymph nodes/gut route, which ameliorated EAE without overt colitis. T helper cell rerouting in EAE was dependent on IL-4, which enhanced retinoic acid (RA) production by dendritic cells, which further induced expression of gut-homing receptors CCR9 and α4β7 on Bcl11b-deficient CD4+ T cells. Furthermore, IL-4 treatment or Th2 immunization of wild-type mice with EAE caused no alteration in Th17 cytokines or RORγt, but diverted T helper cell trafficking to the gut, which improved EAE outcome without overt colitis. Our data demonstrate that Th17 cells are permissive to Th2 gene expression without affecting Th17 gene expression. This Th17 plasticity has an impact on trafficking, which is a critical component of the immune response and may represent a possible avenue for treating multiple sclerosis.
幼稚 T 辅助细胞分化为具有不同功能的效应亚群，驱动专门的免疫反应。最近的研究表明，一些效应亚群具有可塑性。在这里，我们使用 EAE 模型发现，缺乏转录因子 BCL11B 的 Th17 细胞上调了与 Th2 相关的蛋白 GATA3 和 IL-4，而不降低 RAR 相关孤儿受体 γ (RORγt)、IL-17 和 GM-CSF 水平。令人惊讶的是，异常的 IL-4 产生影响了 Th17 细胞的迁移，使其从引流淋巴结/CNS 途径转向肠系膜淋巴结/肠道途径，从而改善了 EAE 而没有明显的结肠炎。EAE 中的辅助性 T 细胞重定向依赖于 IL-4，它增强了树突状细胞的视黄酸（RA）产生，进一步诱导 Bcl11b 缺陷 CD4+T 细胞表达肠道归巢受体 CCR9 和 α4β7。此外，IL-4 治疗或 EAE 野生型小鼠的 Th2 免疫接种没有改变 Th17 细胞因子或 RORγt，但将辅助性 T 细胞的迁移转向肠道，从而改善了 EAE 而没有明显的结肠炎。我们的数据表明，Th17 细胞允许 Th2 基因表达而不影响 Th17 基因表达。这种 Th17 可塑性对迁移有影响，迁移是免疫反应的一个关键组成部分，可能代表治疗多发性硬化症的一种可能途径。
