Laboratory of Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10735-40. doi: 10.1073/pnas.1306691110. Epub 2013 Jun 10.
The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (-/-) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2(-/-) naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2(-/-) naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells.
转录抑制因子 BTB 和 CNC 同源结构域 2（Bach2）被认为主要在具有特定功能的 B 细胞中表达，如类别转换重组和体细胞高频突变，但它在 T 细胞中的功能尚不清楚。我们发现 T 细胞中 Bach2 的表达水平相等，并使用 Bach2 缺陷（-/-）小鼠分析其功能。尽管 T 细胞发育正常，但外周幼稚 T 细胞数量减少，TCR 刺激后迅速产生 Th2 细胞因子。Bach2（-/-）幼稚 T 细胞高度表达与效应记忆 T 细胞相关的基因，如 CCR4、ST-2 和 Blimp-1。这些基因的过度表达诱导 Bach2（-/-）幼稚 T 细胞向 CCR4 配体迁移并对 IL33 作出反应。强制表达 Bach2 可恢复这些基因的表达。通过染色质免疫沉淀（ChIP）-seq 分析，我们确定 S100 钙结合蛋白 a、血红素加氧酶 1 和脯氨酰羟化酶 3 为 Bach2 的直接靶基因，它们在效应记忆 T 细胞中高度表达。这些发现表明 Bach2 抑制效应记忆相关基因以维持幼稚 T 细胞状态，并调节效应记忆 T 细胞的生成。
