Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2012 Nov 1;189(9):4237-46. doi: 10.4049/jimmunol.1201476. Epub 2012 Sep 19.
IL-15 is an important IL-2-related cytokine whose role in Th17 cell biology has not been fully elucidated. In this study, we show that exogenous IL-15 decreased IL-17A production in Th17 cultures. Neutralization of IL-15 using an Ab led to increases in IL-17A production in Th17 cultures. Both Il15(-/-) and Il15r(-/-) T cell cultures displayed higher frequency of IL-17A producers and higher amounts of IL-17A in the supernatants compared with those of wild-type (WT) cells in vitro. IL-15 down-modulated IL-17A production independently of retinoic acid-related orphan receptor-γt, Foxp3, and IFN-γ expression. Both Th17 cells and APCs produced IL-15, which induced binding of STAT5, an apparent repressor to the Il17 locus in CD4 T cells. Also, in a model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), Il15(-/-) mice displayed exacerbated inflammation-correlating with increased IL-17A production by their CD4(+) T cells-compared with WT controls. Exogenous IL-15 administration and IL-17A neutralization reduced the severity of EAE in Il15(-/-) mice. Taken together, these data indicate that IL-15 has a negative regulatory role in fine-tuning of IL-17A production and Th17-mediated inflammation.
白细胞介素-15（IL-15）是一种重要的白细胞介素-2 相关细胞因子，其在 Th17 细胞生物学中的作用尚未完全阐明。在这项研究中，我们表明外源性 IL-15 可减少 Th17 培养物中 IL-17A 的产生。使用 Ab 中和 IL-15 可导致 Th17 培养物中 IL-17A 的产生增加。与野生型（WT）细胞相比，Il15(-/-)和 Il15r(-/-)T 细胞培养物在体外显示出更高频率的 IL-17A 产生细胞和更高水平的上清液中 IL-17A。IL-15 可独立于维甲酸相关孤儿受体-γt、Foxp3 和 IFN-γ表达下调 IL-17A 的产生。Th17 细胞和 APC 均可产生 IL-15，其诱导 STAT5 结合，STAT5 是 CD4 T 细胞中 Il17 基因座的明显抑制剂。此外，在髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎（EAE）模型中，与 WT 对照相比，Il15(-/-)小鼠显示出炎症加重，与其 CD4(+)T 细胞中 IL-17A 产生增加相关。外源性 IL-15 给药和 IL-17A 中和可减轻 Il15(-/-)小鼠的 EAE 严重程度。综上所述，这些数据表明 IL-15 在精细调节 IL-17A 产生和 Th17 介导的炎症中具有负调节作用。
