Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function.
Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function.
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人CD25（+）CD4（+）T调节细胞抑制幼稚和记忆T细胞增殖，可以在体外扩展而不会失去功能。
DOI：
10.1084/jem.193.11.1295
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发表时间：
2001-06-04
影响因子：
15.3
通讯作者：
Roncarolo, M G
中科院分区：
文献类型：
--
作者：
Levings, M K;Sangregorio, R;Roncarolo, M G
调节性T（Tr）细胞的主动抑制作用在下调T细胞对外源和自身抗原的应答中起重要作用。表达CD25的小鼠CD4⁺ Tr细胞在体外以及体内自身免疫疾病模型中具有显著的抑制活性。到目前为止，尚未有人类中存在类似的CD25⁺CD4⁺ Tr细胞亚群的报道。在此我们表明，从外周血分离的人CD25⁺CD4⁺ Tr细胞在T细胞受体介导的多克隆激活时不能增殖，并且CD40配体（CD40L）表达降低，但细胞毒性T淋巴细胞相关抗原（CTLA）-4显著上调。人CD25⁺CD4⁺ Tr细胞对同种异体抗原呈递细胞也不增殖，但它们产生白细胞介素（IL）-10、转化生长因子（TGF）-β、低水平的干扰素（IFN）-γ，不产生IL - 4或IL - 2。重要的是，CD25⁺CD4⁺ Tr细胞强烈抑制初始和记忆CD4⁺ T细胞对同种异体抗原的增殖反应，但它们的抑制作用似乎并不直接需要IL - 10、TGF - β或CTLA - 4。CD25⁺CD4⁺ Tr细胞在IL - 2和同种异体饲养细胞存在的情况下可在体外扩增，并保持其抑制能力。这些发现表明具有免疫抑制作用的CD25⁺CD4⁺ Tr细胞可从外周血中分离并在体外扩增而不丧失功能，这是朝着在T细胞介导的疾病中对这些细胞进行治疗性应用迈出的重要一步。
Active suppression by T regulatory (Tr) cells plays an important role in the downregulation of T cell responses to foreign and self-antigens. Mouse CD4+ Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25+CD4+ Tr cells in humans has not been reported. Here we show that human CD25+CD4+ Tr cells isolated from peripheral blood failed to proliferate and displayed reduced expression of CD40 ligand (CD40L), in response to T cell receptor–mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte–associated antigen (CTLA)-4. Human CD25+CD4+ Tr cells also did not proliferate in response to allogeneic antigen-presenting cells, but they produced interleukin (IL)-10, transforming growth factor (TGF)-β, low levels of interferon (IFN)-γ, and no IL-4 or IL-2. Importantly, CD25+CD4+ Tr cells strongly inhibited the proliferative responses of both naive and memory CD4+ T cells to alloantigens, but neither IL-10, TGF-β, nor CTLA-4 seemed to be directly required for their suppressive effects. CD25+CD4+ Tr cells could be expanded in vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25+CD4+ Tr cells with immunosuppressive effects can be isolated from peripheral blood and expanded in vitro without loss of function represent a major advance towards the therapeutic use of these cells in T cell–mediated diseases.