The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt
The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt
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DOI：
10.1038/ni.1610
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发表时间：
2008-06-01
影响因子：
30.5
通讯作者：
Littman, Dan R.
中科院分区：
文献类型：
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作者：
Manel, Nicolas;Unutmaz, Derya;Littman, Dan R.
T(H)-17细胞是分泌白介素17(IL-17)的CD4(+)T辅助细胞，参与自身免疫性疾病和粘膜免疫。在小鼠的初始CD4(+)T细胞中，IL-17是在IL-6或IL-21和转化生长因子-β(TGF-β)的共同作用下表达的，需要核受体ROR-γt的诱导。有人认为，人TH-17细胞的分化不依赖于转化生长因子-β，因此与小鼠的分化有根本的不同。我们认为，在无血清条件下，转化生长因子-β、IL-1β和IL-6、IL-21或IL-23是诱导人脐血CD_4(+)T细胞表达IL-17的必要条件和充分条件。转化生长因子-β上调ROR-γt的表达，但同时抑制其诱导IL-17的表达。炎性细胞因子解除了这种抑制，并增加了ROR-γ导向的IL-17的表达。在T(H)-17细胞中检测到的其他基因产物包括趋化因子受体CCR6、IL-23受体、IL-17F和IL-26。我们的研究发现，ROR-Gamma t在人类TH-17细胞从初始的CD4(+)T细胞分化过程中具有中心功能，并表明在小鼠和人类中，类似的细胞因子途径参与了这一过程。
T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4(+) T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4(+) T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear receptor ROR gamma t. It has been suggested that the differentiation of human TH-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1 beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4(+) T cells from cord blood. TGF-beta upregulated ROR gamma t expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased ROR gamma t-directed IL-17 expression. Other gene products detected in T(H)-17 cells after ROR gamma t induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify ROR gamma t as having a central function in the differentiation of human TH-17 cells from naive CD4(+) T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.