Nakamura Masataka, Shibata Kensuke, Hatano Shinya, Sato Tetsuya, Ohkawa Yasuyuki, Yamada Hisakata, Ikuta Koichi, Yoshikai Yasunobu
Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
J Immunol. 2015 Jan 1;194(1):243-51. doi: 10.4049/jimmunol.1401619. Epub 2014 Nov 26.
Notch signaling is an important regulator for the development and function of both αβ and γδ T cells, whereas roles of Notch signaling in T cell maintenance remain unclear. We reported previously that the Notch-Hes1 pathway was involved in the intrathymic development of naturally occurring IL-17-producing (IL-17(+)) γδ T cells. To gain insight into additional roles for the Notch axis in the homeostasis of γδ T cells, we performed a genome-wide analysis of Notch target genes and identified the novel promoter site of IL-7Rα driven by the Notch-RBP-Jκ pathway. Constitutive Notch signaling had the potential to induce IL-7Rα expression on γδ T cells in vivo, as well as in vitro, whereas conditional deletion of RBP-Jκ abrogated IL-7Rα expression, but not Hes1 expression, by γδ T cells and selectively reduced the pool size of IL-7Rα(high) IL-17(+) γδ T cells in the periphery. In the absence of IL-7Rα-mediated signaling, IL-17(+) γδ T cells were barely maintained in adult mice. Addition of exogenous IL-7 in vitro selectively expanded IL-17(+) γδ T cells. Thus, our results revealed a novel role for the Notch-RBP-Jκ-IL-7Rα axis that is independent of Hes1 for homeostasis of IL-17(+) γδ T cells.
Notch信号通路是αβ和γδ T细胞发育及功能的重要调节因子，然而Notch信号通路在T细胞维持中的作用仍不清楚。我们之前报道过，Notch-Hes1通路参与天然产生白细胞介素17（IL-17）的γδ T细胞的胸腺内发育。为深入了解Notch轴在γδ T细胞稳态中的其他作用，我们对Notch靶基因进行了全基因组分析，并确定了由Notch-RBP-Jκ通路驱动的IL-7Rα新启动子位点。组成型Notch信号通路在体内和体外均有诱导γδ T细胞表达IL-7Rα的潜力，而条件性缺失RBP-Jκ可消除γδ T细胞的IL-7Rα表达，但不影响Hes1表达，并选择性地减少外周血中IL-7Rα高表达IL-17阳性γδ T细胞的库大小。在缺乏IL-7Rα介导的信号时，成年小鼠中IL-17阳性γδ T细胞几乎无法维持。体外添加外源性IL-7可选择性地扩增IL-17阳性γδ T细胞。因此，我们的结果揭示了Notch-RBP-Jκ-IL-7Rα轴在IL-17阳性γδ T细胞稳态中独立于Hes1的新作用。
