Fu Chunmei, Ma Tianle, Zhou Li, Mi Qing-Sheng, Jiang Aimin
Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202, USA.
Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA.
Int J Mol Sci. 2025 Jun 25;26(13):6078. doi: 10.3390/ijms26136078.
Glycogen synthase kinase-3 (GSK-3)-particularly the GSK-3β isoform-plays a pivotal role in regulating dendritic cell (DC) functions, including maturation, cytokine production, and antigen presentation. In immature DCs, GSK-3β is continuously active, and its inhibition has been shown to enhance DC maturation and function. As a key upstream kinase of β-catenin, GSK-3 inhibition activates β-catenin in both human and murine DCs-a pathway traditionally linked to its immunomodulatory effects. However, our recent findings challenge this paradigm by uncovering β-catenin-independent, dual roles of GSK-3β in DCs. Our study reveals that while GSK-3β enhances DC-mediated cross-priming of CD8 T cells, it concurrently impairs the generation of memory CD8 T cells. These findings have significant implications for vaccine development and cancer immunotherapy, where both effective T-cell priming and durable memory responses are critical. This mini-review provides an in-depth analysis of mechanistic insights into GSK-3β's paradoxical functions and discusses potential strategies to fine-tune GSK-3 activity for optimized immunotherapeutic outcomes.
糖原合酶激酶-3（GSK-3），尤其是GSK-3β亚型，在调节树突状细胞（DC）功能中起关键作用，这些功能包括成熟、细胞因子产生和抗原呈递。在未成熟的DC中，GSK-3β持续活跃，并且其抑制已被证明可增强DC的成熟和功能。作为β-连环蛋白的关键上游激酶，GSK-3抑制在人和小鼠DC中均激活β-连环蛋白，这是一条传统上与其免疫调节作用相关的途径。然而，我们最近的发现通过揭示GSK-3β在DC中不依赖β-连环蛋白的双重作用，对这一范式提出了挑战。我们的研究表明，虽然GSK-3β增强了DC介导的CD8 T细胞交叉启动，但它同时损害了记忆性CD8 T细胞的产生。这些发现对疫苗开发和癌症免疫治疗具有重要意义，在这些领域中，有效的T细胞启动和持久的记忆反应都至关重要。这篇小型综述对GSK-3β矛盾功能的机制见解进行了深入分析，并讨论了微调GSK-3活性以实现优化免疫治疗结果的潜在策略。
