Dendritic cells orchestrate the crosstalk between innate and adaptive immunity. CD8α+ dendritic cells present antigens to CD8+ T cells and elicit cytotoxic T cell responses to viruses, bacteria and tumours1. Although lineage-specific transcriptional regulators of CD8α+ dendritic cell development have been identified2, the molecular pathways that selectively orchestrate CD8α+ dendritic cell function remain elusive. Moreover, metabolic reprogramming is important for dendritic cell development and activation3,4, but metabolic dependence and regulation of dendritic cell subsets are largely uncharacterized. Here we use a data-driven systems biology algorithm (NetBID) to identify a role of the Hippo pathway kinases Mst1 and Mst2 (Mst1/2) in selectively programming CD8α+ dendritic cell function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8α+ dendritic cells relative to CD8α− dendritic cells. Dendritic cell-specific deletion of Mst1/2—but not Lats1 and Lats2 (Lats1/2) or Yap and Taz (Yap/Taz), which mediate canonical Hippo signalling—disrupts homeostasis and function of CD8+ T cells and anti-tumour immunity. Mst1/2-deficient CD8α+ dendritic cells are impaired in presentation of extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8α− dendritic cells that lack Mst1/2 have largely normal function. Mechanistically, compared to CD8α− dendritic cells, CD8α+ dendritic cells exhibit much stronger oxidative metabolism and critically depend on Mst1/2 signalling to maintain bioenergetic activities and mitochondrial dynamics for their functional capacities. Further, selective expression of IL-12 by CD8α+ dendritic cells depends on Mst1/2 and the crosstalk with non-canonical NF-κB signalling. Our findings identify Mst1/2 as selective drivers of CD8α+ dendritic cell function by integrating metabolic activity and cytokine signalling, and highlight that the interplay between immune signalling and metabolic reprogramming underlies the unique functions of dendritic cell subsets.A data-driven analysis helps to identify specific roles of the Hippo signalling kinases Mst1 and Mst2 in integrating metabolic activity and cytokine signalling in dendritic cells, and thereby orchestrating immune cell function.

中文翻译：

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Hippo/Mst 信号耦合 CD8α+ 树突状细胞的代谢状态和免疫功能

树突状细胞协调先天免疫和适应性免疫之间的串扰。CD8α+ 树突状细胞将抗原呈递给 CD8+ T 细胞，并引发对病毒、细菌和肿瘤的细胞毒性 T 细胞反应1。尽管已经确定了 CD8α+ 树突状细胞发育的谱系特异性转录调节因子，但选择性协调 CD8α+ 树突状细胞功能的分子途径仍然难以捉摸。此外，代谢重编程对于树突状细胞的发育和活化很重要 3、4，但树突状细胞亚群的代谢依赖性和调节在很大程度上是未表征的。在这里，我们使用数据驱动的系统生物学算法 (NetBID) 来确定 Hippo 通路激酶 Mst1 和 Mst2 (Mst1/2) 在选择性编程 CD8α+ 树突状细胞功能和代谢中的作用。我们的 NetBID 分析揭示了 CD8α+ 树突状细胞中 Hippo 通路激酶的活性相对于 CD8α- 树突状细胞的显着富集。Mst1/2 的树突状细胞特异性缺失——但不是 Lats1 和 Lats2 (Lats1/2) 或 Yap 和 Taz (Yap/Taz)，它们介导典型的 Hippo 信号传导——破坏 CD8+ T 细胞的稳态和功能以及抗肿瘤免疫。Mst1/2 缺陷型 CD8α+ 树突细胞在向 CD8+ T 细胞呈递细胞外蛋白和同源肽方面受损，而缺乏 Mst1/2 的 CD8α- 树突细胞功能基本正常。从机制上讲，与 CD8α- 树突状细胞相比，CD8α+ 树突状细胞表现出更强的氧化代谢，并且严重依赖 Mst1/2 信号传导来维持生物能量活动和线粒体动力学的功能能力。更远，CD8α+ 树突状细胞对 IL-12 的选择性表达取决于 Mst1/2 以及与非经典 NF-κB 信号传导的串扰。我们的研究结果通过整合代谢活性和细胞因子信号，将 Mst1/2 确定为 CD8α+ 树突细胞功能的选择性驱动因素，并强调免疫信号和代谢重编程之间的相互作用是树突细胞亚群独特功能的基础。数据驱动的分析有助于确定 Hippo 信号激酶 Mst1 和 Mst2 在整合树突状细胞中的代谢活性和细胞因子信号传导中的特定作用，从而协调免疫细胞功能。