Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
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DOI：
10.1093/intimm/dxh165
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发表时间：
2004-11-01
影响因子：
4.4
通讯作者：
Sakaguchi, S
中科院分区：
文献类型：
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作者：
Yagi, H;Nomura, T;Sakaguchi, S
自然产生的CD25(+)CD4(+)调节性T细胞参与维持免疫自我耐受和下调各种免疫反应。最近在小鼠身上的研究表明，编码转录因子Scurfin的Foxp3是CD25(+)CD4(+)调节性T细胞发育和功能的主要调控基因。在这里，我们研究了FOXP3在人CD25(+)CD4(+)调节性T细胞中的作用。FOXP3基因及其蛋白产物在外周CD25(+)CD4(+)T细胞，特别是正常人CD25(+)CD45RO(+)CD4(+)T细胞中优先表达，有趣的是，在一些人类T细胞白血病病毒1型感染的T细胞株中也表达CD25。TCR刺激CD25(-)CD45RO(-)CD4(+)初始T细胞不能在基因或蛋白水平诱导FOXP3的表达。另一方面，FOXP3的体外逆转录病毒基因转移将外周CD25(-)CD45RO(-)CD4(+)初始T细胞转化为类似于CD25(+)CD4(+)调节性T细胞的调节性T细胞表型。例如，转导FOXP3的T细胞在TCR刺激下表现出包括IL-2和IL-10在内的细胞因子的增殖和产生受损，上调CD25和CTL相关抗原-4等调节性T细胞相关分子的表达，并以细胞与细胞接触依赖的方式抑制其他T细胞的体外增殖。因此，人FOXP3是CD25(+)CD4(+)调节性T细胞发育和功能的重要调控基因，可作为CD25(+)CD4(+)调节性T细胞的可靠标志物。此外，通过FOXP3转导由正常初始T细胞产生的调节性T细胞可用于自身免疫性/炎症性疾病的治疗和各种免疫反应的阴性控制。
Naturally occurring CD25(+)CD4(+) regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD25(+)CD4(+) regulatory T cells. Here we examined the role of FOXP3 in human CD25(+)CD4(+) regulatory T cells. The FOXP3 gene and its protein product were preferentially expressed in peripheral CD25(+)CD4(+) T cells, in particular CD25(+)CD45RO(+)CD4(+) T cells in normal individuals and, interestingly, in some human T cell leukemia virus type 1-infected T cell lines, which constitutively express CD25. TCR stimulation of CD25(-)CD45RO(-)CD4(+) naive T cells failed to elicit FOXP3 expression at the gene or protein level. Ex vivo retroviral gene transfer of FOXP3, on the other hand, converted peripheral CD25(-)CD45RO(-)CD4(+) naive T cells into a regulatory T cell phenotype similar to CD25(+)CD4(+) regulatory T cells. For example, FOXP3-transduced T cells exhibited impaired proliferation and production of cytokines including IL-2 and IL-10 upon TCR stimulation, up-regulated the expression of regulatory T cell-associated molecules such as CD25 and CTL-associated antigen-4 and suppressed in vitro proliferation of other T cells in a cell-cell contact-dependent manner. Thus, human FOXP3 is a crucial regulatory gene for the development and function of CD25(+)CD4(+) regulatory T cells, and can be used as their reliable marker. Furthermore, regulatory T cells de novo produced from normal naive T cells by FOXP3 transduction can be instrumental for treatment of autoimmune/inflammatory diseases and negative control of various immune responses.