Sugimoto Naoshi, Oida Takatoku, Hirota Keiji, Nakamura Kyoko, Nomura Takashi, Uchiyama Takashi, Sakaguchi Shimon
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Int Immunol. 2006 Aug;18(8):1197-209. doi: 10.1093/intimm/dxl060. Epub 2006 Jun 13.
Naturally occurring CD25(+)CD4(+) regulatory T cells (Tregs) actively engage in the maintenance of immunologic self-tolerance and immunoregulation. They specifically express the transcription factor Forkhead box P3 (Foxp3) as a master control molecule for their development and function. Although several cell-surface molecules have been reported as Treg-specific markers, such as CD25, glucocorticoid-induced TNFR family-related gene/protein and CTL-associated molecule-4, they are also expressed on activated T cells derived from CD25(-)CD4(+) naive T cells. To identify Treg-specific molecules controlled by Foxp3, we performed DNA microarray analysis by comparing the following pairs of cell populations: fresh CD25(+)CD4(+) T cells versus fresh CD25(-)CD4(+) T cells, activated CD25(+)CD4(+) T cells versus activated CD25(-)CD4(+) T cells and retrovirally Foxp3-transduced CD25(-)CD4(+) T cells versus mock-transduced CD25(-)CD4(+) T cells. We found that the Gpr83, Ecm1, Cmtm7, Nkg7, Socs2 and glutaredoxin genes are predominantly transcribed in fresh and activated natural Treg as well as in Foxp3-transduced cells, while insulin-like 7, galectin-1, granzyme B and helios genes are natural Treg specific but Foxp3 independent. G protein-coupled receptor 83 (Gpr83) expression on the cell surface of natural Treg was confirmed by staining with Gpr83-specific antibody. Retroviral transduction of either group of genes in CD25(-)CD4(+) T cells failed to confer in vitro suppressive activity. Thus, there are several genes that are expressed in a highly Treg-specific fashion. Some of these genes are controlled by Foxp3, and others are not. These genes, in particular, Gpr83, Ecm1 and Helios, could potentially be used as specific markers for natural Treg.
天然存在的CD25(+)CD4(+)调节性T细胞（Tregs）积极参与免疫自身耐受性和免疫调节的维持。它们特异性表达转录因子叉头框P3（Foxp3）作为其发育和功能的主要控制分子。尽管已经报道了几种细胞表面分子作为Treg特异性标志物，如CD25、糖皮质激素诱导的TNFR家族相关基因/蛋白和CTL相关分子-4，但它们也在源自CD25(-)CD4(+)初始T细胞的活化T细胞上表达。为了鉴定受Foxp3控制的Treg特异性分子，我们通过比较以下几对细胞群体进行了DNA微阵列分析：新鲜的CD25(+)CD4(+)T细胞与新鲜的CD25(-)CD4(+)T细胞、活化的CD25(+)CD4(+)T细胞与活化的CD25(-)CD4(+)T细胞以及逆转录病毒转导Foxp3的CD25(-)CD4(+)T细胞与模拟转导的CD25(-)CD4(+)T细胞。我们发现Gpr83、Ecm1、Cmtm7、Nkg7、Socs2和谷氧还蛋白基因在新鲜和活化的天然Treg以及Foxp3转导的细胞中主要转录，而胰岛素样7、半乳糖凝集素-1、颗粒酶B和Helios基因是天然Treg特异性的，但与Foxp3无关。通过用Gpr83特异性抗体染色证实了天然Treg细胞表面上G蛋白偶联受体83（Gpr83）的表达。在CD25(-)CD4(+)T细胞中逆转录病毒转导任何一组基因都未能赋予体外抑制活性。因此，有几个基因以高度Treg特异性的方式表达。其中一些基因受Foxp3控制，而其他基因则不受其控制。这些基因，特别是Gpr
