Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment
Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment
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DOI：
10.1073/pnas.0701171104
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发表时间：
2007-04-10
影响因子：
11.1
通讯作者：
Chatenoud, Lucienne
中科院分区：
文献类型：
--
作者：
You, Sylvaine;Leforban, Bertrand;Chatenoud, Lucienne
先前的结果表明，在1型糖尿病的自发模型--非肥胖糖尿病(NOD)小鼠中，CD4(+)CD25(+)调节性T细胞(Tregs)控制着自身免疫。此外，在这种情况下，抗CD3通过促进以转化生长因子-β依赖的方式发挥作用的Treg来逆转糖尿病。这一发现与大量工作相反，这些工作表明，CD4(+)CD25(高)Tregs以细胞因子无关的方式发挥作用，因此表明另一种类型的Treg在这种情况下是可操作的。我们试图确定在未治疗的NOD小鼠和那些接受抗CD3治疗的NOD小鼠中抑制的基础。我们目前的结果表明，存在于CD4(+)CD25(低)淋巴细胞亚群中的Foxp3(+)细胞亚群以一种依赖于转化生长因子β的方式抑制自发性糖尿病NOD小鼠的T细胞免疫，这是一种典型的“适应性”调节性T细胞的功能特性。这种独特的Treg亚群在NOD小鼠中很明显，但不是正常的，这表明NOD小鼠可能会产生这些适应性Treg，试图调节正在进行的自身免疫。重要的是，在两种不同的体内模型中，这些依赖于转化生长因子β的适应性CD4(+)CD25(低)T细胞可以通过抗CD3免疫疗法从外周血中诱导出来，这与自我耐受的恢复有关。
Previous results have shown that CD4(+)CD25(+) regulatory T cells (Tregs) control autoimmunity in a spontaneous model of type 1 diabetes, the nonobese diabetic (NOD) mouse. Moreover, anti-CD3 reverses diabetes in this setting by promoting Tregs that function in a TGF-beta-dependent manner. This finding contrasts with a large body of work suggesting that CD4(+)CD25(high) Tregs act in a cytokine-independent manner, thus suggesting that another type of Treg is operational in this setting. We sought to determine the basis of suppression both in untreated NOD mice and in those treated with anti-CD3. Our present results show that a subset of foxP3(+) cells present within a CD4(+)CD25(low) lymphocyte subset suppresses T cell immunity in spontaneously diabetic NOD mice in a TGF-beta-dependent manner, a functional propertytypical of "adaptive" regulatory T cells. This distinct Treg subset is evident in NOD, but not normal, mice, suggesting that the NOD mice may generate these adaptive Tregs in an attempt to regulate ongoing autoimmunity. Importantly, in two distinct in vivo models, these TGF-beta-dependent adaptive CD4(+)CD25(low) T cells can be induced from peripheral CD4(+)CD25(-) T lymphocytes by anti-CD3 immunotherapy which correlates with the restoration of self-tolerance.