Shi Min, Lin Tsung H, Appell Kenneth C, Berg Leslie J
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Immunity. 2008 Jun;28(6):763-73. doi: 10.1016/j.immuni.2008.04.016.
Differentiation of naive CD4+ T cells into T helper type 1 (Th1) effector cells requires both T cell receptor (TCR) signaling and cytokines such as interleukin-12 and interferon gamma (IFN-gamma). Here, we report that a third cytokine signal, mediated by the Janus family tyrosine kinase 3 (Jak3) and signal transducer and activator of transcription 5 (STAT5) pathway, is also required for Th1 cell differentiation. In the absence of Jak3-dependent signals, naive CD4+ T cells proliferate robustly but produce little IFN-gamma after Th1 cell polarization in vitro. This defect is not due to reduced activation of STAT1 or STAT4 or to impaired upregulation of the transcription factor T-bet. Instead, we find that T-bet binding to the Ifng promoter is greatly diminished in the absence of Jak3-dependent signals, correlating with a decrease in Ifng promoter accessibility and histone acetylation. These data indicate that Jak3 regulates epigenetic modification and chromatin remodeling of the Ifng locus during Th1 cell differentiation.
初始CD4+ T细胞分化为1型辅助性T细胞（Th1）效应细胞既需要T细胞受体（TCR）信号，也需要诸如白细胞介素-12和干扰素γ（IFN-γ）等细胞因子。在此，我们报告由Janus家族酪氨酸激酶3（Jak3）和信号转导及转录激活因子5（STAT5）途径介导的第三种细胞因子信号对于Th1细胞分化也是必需的。在缺乏Jak3依赖性信号的情况下，初始CD4+ T细胞在体外Th1细胞极化后能强劲增殖，但产生的IFN-γ很少。此缺陷并非由于STAT1或STAT4的激活减少，也不是由于转录因子T-bet的上调受损。相反，我们发现，在缺乏Jak3依赖性信号的情况下，T-bet与Ifng启动子的结合大大减少，这与Ifng启动子可及性和组蛋白乙酰化的降低相关。这些数据表明，Jak3在Th1细胞分化过程中调节Ifng基因座的表观遗传修饰和染色质重塑。
