Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
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DOI：
10.1038/nature04753
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发表时间：
2006-05-11
期刊：
影响因子：
64.8
通讯作者：
Kuchroo, VK
中科院分区：
文献类型：
--
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
激活后，T细胞经历不同的发育途径，获得特殊的特性和效应功能。辅助T细胞（T-H）通常被认为分化为T(H)1和T(H)2细胞亚群。T(H)1细胞对于清除细胞内病原体是必需的，T(H)2细胞对于清除细胞外生物体是重要的（1,2）。最近，一种不同于T(H)1或T(H)2细胞的产生白细胞介素(IL)-17的T(H)17细胞亚群被描述并显示在诱导自身免疫组织损伤中起关键作用（3-5）。相比之下，CD4(+) CD25(+) Foxp3（+）调节性T （T-reg）细胞抑制自身免疫并保护组织免受损伤(6)。转化生长因子- β (tgf - β)是T-reg细胞生成的关键分化因子(7)。我们在小鼠实验中发现，在内源性Foxp3位点引入报告基因后，炎症诱导的急性期蛋白IL-6（8,9）完全抑制tgf - β诱导的Foxp3(+) T-reg细胞的产生。我们还证明IL-23不是T(H)17细胞产生的分化因子。相反，IL-6和tgf - β共同诱导致病性T(H)17细胞从初始T细胞分化。我们的数据显示了诱导自身免疫的致病性（T(H)17） T细胞和抑制自身免疫组织损伤的调节性（Foxp3(+)） T细胞的分化。
On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T-H) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms(1,2). Recently, a subset of interleukin ( IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury(3-5). In contrast, CD4(+) CD25(+) Foxp3(+) regulatory T (T-reg) cells inhibit autoimmunity and protect against tissue injury(6). Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T-reg cells(7). Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation(8,9), completely inhibits the generation of Foxp3(+) T-reg cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3(+)) T cells that inhibit autoimmune tissue injury.