Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible HIV infection
Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible HIV infection
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DOI：
10.4049/jimmunol.180.2.764
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发表时间：
2008-01-15
影响因子：
4.4
通讯作者：
Unutmaz, Derya
中科院分区：
文献类型：
--
作者：
Antons, Amanda K.;Wang, Rui;Unutmaz, Derya
表达转录因子FoxP 3的CD 4（+）CD 25（+）人调节性T细胞（T-reg细胞）抑制T细胞活化。在这项研究中，我们试图确定人类T-reg细胞分化的细胞和分子机制。人幼稚CD 4（+）T细胞的一个亚群是CD 25（+），表达高水平的FoxP 3。我们表明，通过TCR激活后，这些FoxP 3表达幼稚T细胞（称为T-Nreg细胞）在体外大大扩增。扩增的T-Nreg细胞获得具有有效抑制活性的完整Treg表型，并且在TCR刺激后显示低IL-2产生。通过RNA干扰降低FoxP 3表达的T-Nreg细胞失去了它们的抑制活性，但保留了它们对TCR刺激的低IL-2分泌。此外，为了支持T-Nreg细胞代表幼稚细胞的独立谱系的观点，我们发现与幼稚CD 4（+）T细胞相比，它们更容易感染HIV。基于这些发现，我们提出T-Nreg细胞是人类T-reg细胞的前体，并且这些细胞需要高水平的FoxP 3表达来维持其抑制功能。因此，在感染如HIV期间调节T-Nreg细胞数量可能会破坏人T-reg细胞发育，并有助于慢性免疫激活。
CD4(+)CD25(+) human regulatory T cells (T-reg cells), which express the transcription factor FoxP3, suppress T cell activation. In this study, we sought to define cellular and molecular mechanisms of human T-reg cell differentiation. A subset of human naive CD4(+) T cells that are CD25(+) express high levels of FoxP3. We show that upon activation through the TCR, these FoxP3-expressing naive T cells (termed T-Nreg cells) greatly expand in vitro. Expanded T-Nreg cells acquire a full Treg phenotype with potent suppressive activity and display low IL-2 production upon TCR stimulation. T-Nreg cells in which FoxP3 expression was reduced through RNA interference lost their suppressive activity, but retained their low IL-2 secretion in response to TCR stimulation. Furthermore, in support of the notion that T-Nreg cells represent a separate lineage of naive cells, we found that they were more susceptible to HIV infection as compared with naive CD4(+) T cells. Based on these findings, we propose that T-Nreg cells are precursors for human T-reg cells and that these cells require a high level of FoxP3 expression to maintain their suppressive function. Accordingly, modulation of T-Nreg cell numbers during infections such as HIV may disrupt human T-reg cell development, and contribute to chronic immune activation.