LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells

Liver Kinase B1 (LKB1) plays a key role in cellular metabolism by controlling AMPK activation. However, its function in dendritic cell (DC) biology has not been addressed. Here, we find that LKB1 functions as a critical brake on DC immunogenicity, and when lost, leads to reduced mitochondrial fitness and increased maturation, migration, and T cell priming of peripheral DCs. Concurrently, loss of LKB1 in DCs enhances their capacity to promote output of regulatory T cells (Tregs) from the thymus, which dominates the outcome of peripheral immune responses, as suggested by increased resistance to asthma and higher susceptibility to cancer in CD11c?LKB1 mice. Mechanistically, we find that loss of LKB1 specifically primes thymic CD11b+ DCs to facilitate thymic Treg development and expansion, which is independent from AMPK signalling, but dependent on mTOR and enhanced phospholipase C ß1-driven CD86 expression. Together, our results identify LKB1 as a critical regulator of DC-driven effector T cell and Treg responses both in the periphery and the thymus. Overall design: Thymic Dendritic cells subsets (cDC1, cDC2 and pDC) from WT and LKB1 KO mice were isolated from thymi and analyzed.肝脏激酶B1（LKB1）通过调控AMP活化蛋白激酶（AMPK）的激活，在细胞代谢中发挥关键作用。然而，其在树突状细胞（DC）生物学中的功能尚未被阐明。本研究发现，LKB1是树突状细胞免疫原性的关键负调控因子；当LKB1缺失时，外周树突状细胞的线粒体适应性受损，同时其成熟、迁移及T细胞致敏能力显著增强。与此同时，树突状细胞中LKB1的缺失可增强其促进胸腺调节性T细胞（Tregs）生成的能力，这一效应主导了外周免疫应答的走向——CD11c特异性LKB1敲除小鼠表现出哮喘抵抗能力增强及肿瘤易感性升高，与上述发现一致。机制层面的研究显示，LKB1的缺失可特异性致敏胸腺CD11b阳性树突状细胞，以促进胸腺Treg的发育与扩增；这一过程不依赖于AMPK信号通路，而是依赖于哺乳动物雷帕霉素靶蛋白（mTOR）及磷脂酶Cβ1介导的CD86分子表达上调。综上，本研究证实LKB1是调控外周及胸腺内树突状细胞介导的效应T细胞与调节性T细胞应答的关键因子。实验整体设计：从野生型（WT）及LKB1敲除（KO）小鼠的胸腺中分离树突状细胞亚群（cDC1、cDC2及pDC）并开展分析。