Pyaram Kalyani, Sen Jyoti Misra, Chang Cheong-Hee
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD 217287, USA.
Mol Immunol. 2017 May;85:47-56. doi: 10.1016/j.molimm.2017.01.025. Epub 2017 Feb 14.
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.
Wnt/β-连环蛋白信号通路在包括免疫细胞存活和增殖在内的各种细胞功能中发挥着重要作用。该通路在传统T细胞发育中的关键作用已得到确立，但对其在天然T细胞发育中的作用知之甚少。在本研究中，我们发现，β-连环蛋白水平（Wnt/β-连环蛋白信号强度的一个指标）在恒定自然杀伤T细胞（iNKT）发育过程中受到调控。在从双阳性胸腺细胞选择iNKT细胞至iNKT细胞发育的0期以及随后发育至1期的过程中，β-连环蛋白水平大幅升高。此后，β-连环蛋白水平从2期开始下降，而2期对iNKT细胞的终末成熟至关重要。在表达稳定活性形式β-连环蛋白（CATtg）的小鼠中，未能抑制Wnt/β-连环蛋白信号导致2期iNKT细胞增加，3期iNKT细胞减少。CATtg iNKT细胞从2期到3期的低效转变似乎是由于IL-15R（CD122）和转录因子T-bet表达不佳所致，这两者都是胸腺中iNKT细胞终末成熟所必需的。因此，CATtg小鼠中IFN-γ+ iNKT细胞大幅减少。总之，我们的研究结果表明，β-连环蛋白的适当调控以及由此而来的Wnt信号在iNKT细胞的终末成熟和功能中起着重要作用。
