Naoe Yoshinori, Setoguchi Ruka, Akiyama Kaori, Muroi Sawako, Kuroda Masahiko, Hatam Farah, Littman Dan R, Taniuchi Ichiro
Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Turumi-ku, Yokohama, Kanagawa 230-0045, Japan.
J Exp Med. 2007 Aug 6;204(8):1749-55. doi: 10.1084/jem.20062456. Epub 2007 Jul 23.
Interferon gamma (IFN gamma) is the hallmark cytokine produced by T helper type 1 (Th1) cells, whereas interleukin (IL)-4 is the hallmark cytokine produced by Th2 cells. Although previous studies have revealed the roles of cytokine signaling and of transcription factors during differentiation of Th1 or Th2 cells, it is unclear how the exclusive expression pattern of each hallmark cytokine is established. The DNaseI hypersensitivity site IV within the mouse Il4 locus plays an important role in the repression of Il4 expression in Th1 cells, and it has been named the Il4 silencer. Using Cbf beta- or Runx3-deficient T cells, we show that loss of Runx complex function results in derepression of IL-4 in Th1 cells. Binding of Runx complexes to the Il4 silencer was detected in naive CD4(+) T cells and Th1 cells, but not in Th2 cells. Furthermore, enforced expression of GATA-3 in Th1 cells inhibited binding of Runx complexes to the Il4 silencer. Interestingly, T cell-specific inactivation of the Cbf beta gene in mice led to elevated serum immunoglobulin E and airway infiltration. These results demonstrate critical roles of Runx complexes in regulating immune responses, at least in part, through the repression of the Il4 gene.
干扰素γ（IFNγ）是1型辅助性T细胞（Th1）产生的标志性细胞因子，而白细胞介素（IL）-4是Th2细胞产生的标志性细胞因子。尽管先前的研究已经揭示了细胞因子信号传导和转录因子在Th1或Th2细胞分化过程中的作用，但尚不清楚每种标志性细胞因子的特异性表达模式是如何建立的。小鼠Il4基因座内的DNA酶I超敏位点IV在Th1细胞中Il4表达的抑制中起重要作用，它被命名为Il4沉默子。使用Cbfβ或Runx3缺陷型T细胞，我们发现Runx复合物功能的丧失导致Th1细胞中IL-4的去抑制。在初始CD4(+) T细胞和Th1细胞中检测到Runx复合物与Il4沉默子的结合，但在Th2细胞中未检测到。此外，在Th1细胞中强制表达GATA-3会抑制Runx复合物与Il4沉默子的结合。有趣的是，小鼠中Cbfβ基因的T细胞特异性失活导致血清免疫球蛋白E升高和气道浸润。这些结果表明Runx复合物在调节免疫反应中起关键作用，至少部分是通过抑制Il4基因来实现的。
