Mathur Anubhav N, Chang Hua-Chen, Zisoulis Dimitrios G, Stritesky Gretta L, Yu Qing, O'Malley John T, Kapur Reuben, Levy David E, Kansas Geoffrey S, Kaplan Mark H
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J Immunol. 2007 Apr 15;178(8):4901-7. doi: 10.4049/jimmunol.178.8.4901.
IL-17-secreting CD4(+) T cells are critically involved in inflammatory immune responses. Development of these cells is promoted in vivo and in vitro by IL-23 or TGFbeta1 plus IL-6. Despite growing interest in this inflammatory Th subset, little is known about the transcription factors that are required for their development. We demonstrate that Stat3 is required for programming the TGFbeta1 plus IL-6 and IL-23-stimulated IL-17-secreting phenotype, as well as for RORgammat expression in TGFbeta1 plus IL-6-primed cells. Moreover, retroviral transduction of a constitutively active Stat3 into differentiating T cell cultures enhances IL-17 production from these cells. We further show that Stat4 is partially required for the development of IL-23-, but not TGFbeta1 plus IL-6-primed IL-17-secreting cells, and is absolutely required for IL-17 production in response to IL-23 plus IL-18. The requirements for Stat3 and Stat4 in the development of these IL-17-secreting subsets reveal additional mechanisms in Th cell fate decisions during the generation of proinflammatory cell types.
分泌白细胞介素-17（IL-17）的CD4(+) T细胞在炎症性免疫反应中起关键作用。体内和体外实验均表明，IL-23或转化生长因子β1（TGFβ1）加白细胞介素-6（IL-6）可促进这些细胞的发育。尽管人们对这一炎症性辅助性T细胞亚群的兴趣与日俱增，但对其发育所需的转录因子却知之甚少。我们发现，信号转导及转录激活因子3（Stat3）对于设定TGFβ1加IL-6以及IL-23刺激下分泌IL-17的细胞表型，以及在TGFβ1加IL-6预处理细胞中维甲酸相关孤核受体γt（RORγt）的表达而言是必需的。此外，将组成型激活的Stat3通过逆转录病毒转导至分化中的T细胞培养物中，可增强这些细胞分泌IL-17的能力。我们还进一步表明，Stat4对于IL-23预处理而非TGFβ1加IL-6预处理的分泌IL-17细胞的发育是部分必需的，且对于响应IL-23加IL-18产生IL-17而言是绝对必需的。这些分泌IL-17亚群发育过程中对Stat3和Stat4的需求揭示了促炎细胞类型生成过程中辅助性T细胞命运决定的其他机制。
