IL-21 and TGF-β are required for differentiation of human TH17 cells
IL-21 and TGF-β are required for differentiation of human TH17 cells
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DOI：
10.1038/nature07021
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发表时间：
2008-07-17
期刊：
影响因子：
64.8
通讯作者：
Hafler, David A.
中科院分区：
文献类型：
--
作者：
Yang, Li;Anderson, David E.;Hafler, David A.
最近发现的以分泌白细胞介素（IL）-17（T（H）17细胞）和天然存在的调节性FOXP 3（+）CD 4 T细胞（nT（reg））为特征的CD 4（+）T细胞对我们理解T（H）1/T（H）2范式不容易解释的免疫过程产生了重大影响。T（H）17和nT（reg）细胞与人类自身免疫性疾病的发病机制有关，包括多发性硬化症、类风湿性关节炎、炎性肠病和银屑病（1，2）。我们最近的数据和其他人的工作表明，转化生长因子-β（TGF-β）和IL- 6负责幼稚小鼠T细胞分化为T（H）17细胞，并且已经提出IL-23可能在稳定T（H）17表型中起关键作用（3-5）。已经发现了第二种途径，其中TGF-β和IL- 21的组合能够在不存在IL- 6的情况下诱导小鼠T（H）17细胞的分化（参考文献6 - 8）。然而，TGF-β和IL- 6不能分化人T（H）17细胞（2，9），并且已经表明TGF-β实际上可能抑制人T（H）17细胞的产生（10）。相反，最近已经显示细胞因子IL-1 β、IL- 6和IL- 23能够在从人外周血分离的短期CD 4（+）T细胞系中驱动IL- 17分泌（11），尽管幼稚人CD 4细胞分化为T（H）17细胞所需的因子仍然未知。在此，我们证实了IL-1 β和IL- 6诱导人中央记忆CD 4（+）T细胞分泌IL-17 A，而TGF-β和IL- 21独特地促进人幼稚CD 4（+）T细胞分化为T（H）17细胞，并伴随转录因子RORC 2的表达。这些数据将允许在人类炎症性疾病中研究这种新的T（H）17细胞群。
The recent discovery of CD4(+) T cells characterized by secretion of interleukin ( IL)- 17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell ( nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis(1,2). Our recent data and the work of others demonstrated that transforming growth factor-beta ( TGF-beta) and IL- 6 are responsible for the differentiation of naive mouse T cells into T(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T(H)17 phenotype(3-5). A second pathway has been discovered in which a combination of TGF-beta and IL- 21 is capable of inducing differentiation of mouse T(H)17 cells in the absence of IL- 6 ( refs 6 - 8). However, TGF-beta and IL- 6 are not capable of differentiating human T(H)17 cells(2,9) and it has been suggested that TGF-beta may in fact suppress the generation of human T(H)17 cells(10). Instead, it has been recently shown that the cytokines IL-1 beta, IL- 6 and IL- 23 are capable of driving IL- 17 secretion in short- term CD4(+) T cell lines isolated from human peripheral blood(11), although the factors required for differentiation of naive human CD4 to T(H)17 cells are still unknown. Here we confirm that whereas IL-1 beta and IL- 6 induce IL- 17A secretion from human central memory CD4(+) T cells, TGF-beta and IL- 21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T(H)17 cells in human inflammatory disease.