T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine.
T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine.
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DOI：
10.1038/ncomms11627
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发表时间：
2016-05-19
影响因子：
16.6
通讯作者：
Powrie F
中科院分区：
文献类型：
--
作者：
Krausgruber T;Schiering C;Adelmann K;Harrison OJ;Chomka A;Pearson C;Ahern PP;Shale M;Oukka M;Powrie F
IL-23 是致病性 Th17 细胞反应的关键驱动因素。有人提出，转录因子 T-bet 是促进 IL-23 驱动的致病效应功能所必需的；然而，T-bet 在肠道 T 细胞反应中的确切作用仍然难以捉摸。在这里，我们表明 T 细胞的 T-bet 表达并不是诱导结肠炎或致病性 Th17 细胞分化所必需的，而是通过负向调节 IL-23R 表达来改变 IL-23 驱动的结肠炎反应的定性特征。因此，T-bet 的缺失会导致 Th17 细胞分化和激活不受限制，其特征是产生大量 IL-17A 和 IL-22。 IL-17A/IL-22 的联合增加导致上皮细胞活化增强，而 IL-17A 或 IL-22 的抑制则导致疾病改善。我们的研究确定 T-bet 是肠道内 IL-23 驱动的结肠炎反应的关键调节剂，对于理解炎症性肠病患者的异质性具有重要意义。 转录因子 T-bet 和 Th17 细胞如何导致结肠炎仍不完全清楚。在这里，作者将 T-bet 确定为 IL-23R 通路激活的负调节因子，并表明 T-bet 缺陷的 T 细胞驱动依赖于细胞因子 IL-17A 和 IL-22 的致结肠炎 Th17 反应。
IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T cells is not required for the induction of colitis or the differentiation of pathogenic Th17 cells but modifies qualitative features of the IL-23-driven colitogenic response by negatively regulating IL-23R expression. Consequently, absence of T-bet leads to unrestrained Th17 cell differentiation and activation characterized by high amounts of IL-17A and IL-22. The combined increase in IL-17A/IL-22 results in enhanced epithelial cell activation and inhibition of either IL-17A or IL-22 leads to disease amelioration. Our study identifies T-bet as a key modulator of IL-23-driven colitogenic responses in the intestine and has important implications for understanding of heterogeneity among inflammatory bowel disease patients. How transcription factor T-bet and Th17 cells contribute to colitis remains incompletely understood. Here the authors identify T-bet as a negative regulator of IL-23R pathway activation and show that T-bet deficient T cells drive colitogenic Th17 responses dependent on the cytokines IL-17A and IL-22.