Temporal regulation of Wnt/β-catenin signaling is important for invariant NKT cell development and terminal maturation.
Temporal regulation of Wnt/β-catenin signaling is important for invariant NKT cell development and terminal maturation.
复制标题
DOI：
10.1016/j.molimm.2017.01.025
复制
发表时间：
2017-05
影响因子：
3.6
通讯作者：
Chang CH
中科院分区：
文献类型：
--
作者：
Pyaram K;Sen JM;Chang CH
Wnt/β-catenin信号通路在包括免疫细胞的存活和增殖在内的各种细胞功能中发挥重要作用。该途径在常规T细胞发育中的关键作用已经确立，但对其对先天性T细胞发育的贡献知之甚少。在这项研究中，我们发现β-catenin水平，Wnt/β-catenin信号强度的指示，在不变NKT（iNKT）细胞发育过程中受到调节。在iNKT细胞从双阳性胸腺细胞选择至iNKT细胞发育的第0阶段期间以及在随后发育至第1阶段期间，β-连环蛋白水平大大增加。此后，β-连环蛋白水平从第2阶段降低，这对于iNKT细胞的终末成熟是必需的。在表达稳定活性形式的β-连环蛋白（CATtg）的小鼠中未能抑制Wnt/β-连环蛋白信号传导导致第2阶段iNKT细胞增加和第3阶段iNKT细胞减少。CATtg iNKT细胞中从第2阶段到第3阶段的无效转变似乎是由IL-15 R（CD 122）和转录因子T-bet的表达差造成的，这两者对于胸腺中iNKT细胞的终末成熟都是必需的。因此，CATtg小鼠中IFN-γ+ iNKT细胞大大减少。总之，我们的研究结果表明，β-catenin和Wnt信号的适当调节在iNKT细胞的终末成熟和功能中起着重要作用。
The Wnt/β-catenin signaling pathway plays important roles during various cellular functions including survival and proliferation of immune cells. The critical role of this pathway in conventional T cell development is established but little is known about its contributions to innate T cell development. In this study, we found that β-catenin level, an indication of the strength of Wnt/β-catenin signaling, is regulated during invariant NKT (iNKT) cell development. β-catenin levels were greatly increased during iNKT cell selection from double positive thymocytes to Stage 0 of iNKT cell development and during subsequent development to Stage 1. Thereafter, β-catenin levels decrease from Stage 2, which is essential for the terminal maturation of iNKT cells. Failure to dampen Wnt/β-catenin signaling as in mice expressing a stabilized active form of β-catenin (CATtg) resulted in increased Stage 2 and decreased Stage 3 iNKT cells. Inefficient transition from Stage 2 to 3 in CATtg iNKT cells seems to be contributed by poor expression of IL-15R (CD122) and transcription factor T-bet, both of which are necessary for terminal maturation of iNKT cells in the thymus. Consequently, IFN-γ+ iNKT cells were greatly reduced in CATtg mice. Together, our findings reveal that proper regulation of β-catenin and in turn Wnt signaling plays an important role in the terminal maturation and function of iNKT cells.