Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor
Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor
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DOI：
10.1016/j.immuni.2009.03.019
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发表时间：
2009-06-19
期刊：
影响因子：
32.4
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
--
作者：
Miyara, Makoto;Yoshioka, Yumiko;Sakaguchi, Shimon
FoxP3 是天然 CD4+ 调节性 T 细胞（Treg 细胞）发育和功能的关键转录因子。在这里，我们发现人类 FoxP3(+)CD4(+) T 细胞由三个表型和功能不同的亚群组成：CD45RA(+)FoxP3(lo) 静息 Treg 细胞（rTreg 细胞）和 CD45RA(-)FoxP3(hi) 激活的 Treg 细胞（aTreg 细胞），两者在体外均具有抑制性，以及分泌细胞因子的 CD45RA(-)FoxP3(lo) 非抑制性 T 细胞。脐带血、老年人和免疫性疾病患者这三个亚群的比例有所不同。终末分化的aTreg细胞迅速死亡，而rTreg细胞在体外和体内增殖并转化为aTreg细胞。将 rTreg 细胞转移到 NOD-scid-common 伽马链缺陷小鼠中，以及在正常个体的外周血中基于 TCR 序列的 T 细胞克隆型追踪显示了这一点。总而言之，将 FoxP3(+) 细胞分解为亚群，使人们能够分析正常和疾病状态下 Treg 细胞的分化动态和相互作用，并通过操纵特定的 FoxP3(+) 亚群来控制免疫反应。
FoxP3 is a key transcription factor for the development and function of natural CD4(+) regulatory T cells (Treg cells). Here we show that human FoxP3(+)CD4(+) T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA(+)FoxP3(lo) resting Treg cells (rTreg cells) and CD45RA(-)FoxP3(hi) activated Treg cells (aTreg cells), both of which were suppressive in vitro, and cytokine-secreting CD45RA(-)FoxP3(lo) nonsuppressive T cells. The proportion of the three subpopulations differed between cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTreg cells rapidly died whereas rTreg cells proliferated and converted into aTreg cells in vitro and in vivo. This was shown by the transfer of rTreg cells into NOD-scid-common gamma-chain-deficient mice and by TCR sequence-based T cell clonotype tracing in peripheral blood in a normal individual. Taken together, the dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3(+) subpopulations.