Department of Microbiology and Immunology, Vanderbilt University, Nashville TN 37232, USA.
J Immunol. 2013 Jul 15;191(2):678-87. doi: 10.4049/jimmunol.1203360. Epub 2013 Jun 12.
CD4(+) T cells developing toward a Th2 fate express IL-4, IL-5, and IL-13 while inhibiting production of cytokines associated with other Th types, such as the Th1 cytokine IFN- γ. IL-4-producing Th2 effector cells give rise to a long-lived memory population committed to reactivation of the Th2 cytokine gene expression program. However, reactivation of these effector-derived cells under Th1-skewing conditions leads to production of IFN-γ along with IL-4 in the same cell. We now show that this flexibility ("plasticity") of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization yet requires STAT4 along with T-box expressed in T cells. Surprisingly, loss of either STAT4 or T-box expressed in T cells increased Ifng promoter CpG methylation in both effector and memory Th2 cells. Taken together, our data suggest a model in which the expression of IFN-γ by Th2-derived memory cells involves attenuation of epigenetic repression in memory Th2 cells, combined with Th1-polarizing signals after their recall activation.
CD4(+) T 细胞向 Th2 命运发展时表达 IL-4、IL-5 和 IL-13，同时抑制与其他 Th 类型相关的细胞因子的产生，如 Th1 细胞因子 IFN-γ。产生 IL-4 的 Th2 效应细胞产生一个长寿命的记忆群体，致力于重新激活 Th2 细胞因子基因表达程序。然而，在 Th1 偏向条件下，这些效应细胞的重新激活导致同一细胞中同时产生 IFN-γ 和 IL-4。我们现在表明，这种细胞因子表达的灵活性（“可塑性”）是在 Th2 极化过程中获得的 Ifng 启动子的抑制性 DNA 甲基化丧失之前发生的，但需要 STAT4 和 T 细胞中表达的 T 框。令人惊讶的是，STAT4 或 T 细胞中表达的 T 框的缺失都会增加效应器和记忆性 Th2 细胞中 Ifng 启动子的 CpG 甲基化。总之，我们的数据表明，Th2 衍生的记忆细胞中 IFN-γ 的表达涉及在记忆性 Th2 细胞中减弱表观遗传抑制，以及在其重新激活后的 Th1 极化信号。
