Distinct regulation of interleukin-17 in human T helper lymphocytes
Distinct regulation of interleukin-17 in human T helper lymphocytes
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DOI：
10.1002/art.22866
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发表时间：
2007-09-01
影响因子：
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通讯作者：
O'Shea, John J.
中科院分区：
文献类型：
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作者：
Chen, Zhi;Tato, Cristina M.;O'Shea, John J.
目标。产生白介素17(IL-17)的辅助性T细胞被认为是一个独立的CD4+细胞谱系，被称为Th17细胞，受转录因子视黄酸相关孤儿受体-γt(ROR-Gamma t)的调节。然而，尽管在理解小鼠Th17分化方面取得了进展，但对促进原始人类T细胞向Th17细胞分化的因素的系统评估尚未见报道。本研究旨在评估已知的促进小鼠Th17细胞的细胞因子对人类幼稚的CD4+T细胞的影响。从人外周血中分离出幼稚和记忆性的CD4+T细胞，并用不同的细胞因子进行激活和培养。采用酶联免疫吸附试验和流式细胞仪检测细胞因子的产生。采用定量聚合酶链式反应检测信使RNA。在单独抗CD3/抗CD28刺激下，人记忆T细胞迅速产生IL-17，而幼稚T细胞低水平表达。转化生长因子β1和IL-6可上调初始CD4+T细胞的ROR-γt表达，但不能诱导其向Th17分化。而IL-23上调自身受体，是IL-17和IL-22的重要诱导物。目前的数据表明，与小鼠细胞相比，人CD4+T细胞对IL-17和ROR-γt表达的调节存在差异。从小鼠幼稚前体细胞培养产生IL-17的T细胞的最佳条件对人类T细胞无效。相反，IL-23促进人类Th17细胞的产生，但也是其他促炎细胞因子的非常有效的诱导剂。与小鼠模型相比，这些发现可能对人类自身免疫的发病机制有重要的意义。
Objective. Interleukin-17 (IL-17)-producing T helper cells have been proposed to represent a separate lineage of CD4+ cells, designated Th17 cells, which are regulated by the transcription factor retinoic acid-related orphan receptor -gamma t (ROR gamma t). However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naive human T cells to Th17 cells has not been reported. The present study was undertaken to assess the effects on naive human CD4+ T cells of cytokines known to promote murine Th17 cells.Methods. Human naive and memory CD4+ T cells isolated from peripheral blood were activated and cultured with various cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay and flow cytometry. Messenger RNA was measured by quantitative polymerase chain reaction.Results. In response to anti-CD3/anti-CD28 stimulation alone, human memory T cells rapidly produced IL-17, whereas naive T cells expressed low levels. Transforming growth factor beta 1 and IL-6 up-regulated ROR gamma t expression but did not induce Th17 differentiation of naive CD4+ T cells. However, IL-23 up-regulated its own receptor and was an important inducer of IL-17 and IL-22.Conclusion. The present data demonstrate the differential regulation of IL-17 and ROR gamma t expression in human CD4+ T cells compared with murine cells. Optimal conditions for the development of IL-17-producing T cells from murine naive precursors are ineffective in human T cells. Conversely, IL-23 promoted the generation of human Th17 cells but was also a very potent inducer of other proinflammatory cytokines. These findings may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.