Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
J Immunol. 2012 May 15;188(10):4846-57. doi: 10.4049/jimmunol.1103799. Epub 2012 Apr 13.
IL-4 plays an important role in the induction of Th2 and Th9 cells, as well as in the inhibition of Th1 cell generation. We show that a combination of IL-4 and TGF-β augments the development of Th1 cells that express CD103 (CD103(+) Th1 cells) if IFN-γ is present. The T-box-containing transcription factor eomesodermin (Eomes) is preferentially expressed in CD103(+) Th1 cells and is involved in IFN-γ production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFN-γ gene loci. TGF-β is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6-signaling pathway. IFN-γ-producing CD103(+) Th1 cells are detected in the intraepithelial lymphocytes of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. To our knowledge, these results represent the first molecular mechanism of IL-4/TGF-β-dependent augmentation of Th1 cell generation and raise the possibility that IL-4 and TGF-β simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions.
IL-4 在诱导 Th2 和 Th9 细胞以及抑制 Th1 细胞生成中发挥重要作用。我们表明，如果存在 IFN-γ，IL-4 和 TGF-β 的组合会增强表达 CD103 的 Th1 细胞（CD103(+) Th1 细胞）的发育。T 盒包含转录因子 eomesodermin（Eomes）优先在 CD103(+) Th1 细胞中表达，并参与 IFN-γ 的产生。在早期 T 细胞激活过程中诱导 T-bet 对于在 Eomes 和 IFN-γ 基因座处形成活性染色质是必需的。TGF-β 对于诱导 Eomes 和 CD103 以及抑制 Th2 细胞因子表达是必需的。此外，IL-4 通过激活 Stat6 信号通路诱导 Eomes 转录。在正常小鼠的上皮内淋巴细胞中检测到产生 IFN-γ 的 CD103(+) Th1 细胞，并且在 Tbet 和 Stat6 缺陷小鼠中其数量显著减少。据我们所知，这些结果代表了 IL-4/TGF-β 依赖性增强 Th1 细胞生成的第一个分子机制，并提出了 IL-4 和 TGF-β 可能在某些细胞因子条件下同时增强 Th1 细胞介导的免疫反应的可能性。
