Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells

Abstract

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 tumours ¹ . Although lineage-specific transcriptional regulators of CD8α⁺ dendritic cell development have been identified ² , the molecular pathways that selectively orchestrate CD8α⁺ dendritic cell function remain elusive. Moreover, metabolic reprogramming is important for dendritic cell development and activation^3,4, 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.