Suzuki Junpei, Maruyama Saho, Tamauchi Hidekazu, Kuwahara Makoto, Horiuchi Mika, Mizuki Masumi, Ochi Mizuki, Sawasaki Tatsuya, Zhu Jinfang, Yasukawa Masaki, Yamashita Masakatsu
Department of Haematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Department of Translational Immunology, Translational Research Center, Ehime University Hospital, Toon, Ehime, Japan.
Immunology. 2016 Apr;147(4):476-87. doi: 10.1111/imm.12580. Epub 2016 Feb 9.
A transcriptional repressor Gfi1 promotes T helper type 2 (Th2) cell development and inhibits Th17 and inducible regulatory T-cell differentiation. However, the role of Gfi1 in regulating Th1 cell differentiation and the Th1-type immune response remains to be investigated. We herein demonstrate that Gfi1 inhibits the induction of the Th1 programme in activated CD4 T cells. The activated Gfi1-deficient CD4 T cells spontaneously develop into Th1 cells in an interleukin-12- and interferon-γ-independent manner. The increase of Th1-type immune responses was confirmed in vivo in Gfi1-deficient mice using a murine model of nickel allergy and delayed-type hypersensitivity (DTH). The expression levels of Th1-related transcription factors were found to increase in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 were identified as possible direct targets of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and reduces the histone H3K4 methylation levels in part by modulating Lsd1 recruitment. Together, these findings demonstrate a novel regulatory role of Gfi1 in the regulation of the Th1-type immune response.
转录抑制因子Gfi1促进2型辅助性T细胞（Th2）发育，并抑制Th17和诱导性调节性T细胞分化。然而，Gfi1在调节Th1细胞分化和Th1型免疫反应中的作用仍有待研究。我们在此证明，Gfi1抑制活化的CD4 T细胞中Th1程序的诱导。活化的Gfi1缺陷型CD4 T细胞以不依赖白细胞介素-12和干扰素-γ的方式自发发育为Th1细胞。使用镍过敏和迟发型超敏反应（DTH）小鼠模型，在Gfi1缺陷型小鼠体内证实了Th1型免疫反应增强。发现Th1相关转录因子的表达水平在Gfi1缺陷的活化CD4 T细胞中增加。Tbx21、Eomes和Runx2被确定为Gfi1可能的直接靶标。Gfi1与Tbx21、Eomes和Runx2基因位点结合，并通过调节Lsd1募集部分降低组蛋白H3K4甲基化水平。总之，这些发现证明了Gfi1在调节Th1型免疫反应中的新调控作用。
