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Hippo/Mst signalling couples metabolic state and immune function of CD8?+ dendritic cells.

ABSTRACT: Dendritic cells orchestrate the crosstalk between innate and adaptive immunity. CD8?+ 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 CD8?+ dendritic cell development have been identified 2 , the molecular pathways that selectively orchestrate CD8?+ 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 CD8?+ dendritic cell function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8?+ dendritic cells relative to CD8?- 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 CD8?+ dendritic cells are impaired in presentation of extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8?- dendritic cells that lack Mst1/2 have largely normal function. Mechanistically, compared to CD8?- dendritic cells, CD8?+ 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 CD8?+ dendritic cells depends on Mst1/2 and the crosstalk with non-canonical NF-?B signalling. Our findings identify Mst1/2 as selective drivers of CD8?+ 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.

SUBMITTER: Du X

PROVIDER: S-EPMC6292204 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Du Xingrong X Wen Jing J Wang Yanyan Y Karmaus Peer W F PWF Khatamian Alireza A Tan Haiyan H Li Yuxin Y Guy Cliff C Nguyen Thanh-Long M TM Dhungana Yogesh Y Neale Geoffrey G Peng Junmin J Yu Jiyang J Chi Hongbo H

Nature 20180530 7708

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, me ...[more]

PMID: 29849151

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Project description:Asthma is an allergic lung disease and, when associated to cigarette smoke exposition, some patients show controversial signs about lung function and other inflammatory mediators. Epidemiologic and experimental studies have shown both increasing and decreasing inflammation in lungs of subjects with asthma and exposed to cigarette smoke. Therefore, in this study, we analyzed how cigarette smoke affects pro-inflammatory and anti-inflammatory mediators in a murine model of allergic pulmonary inflammation. We sensitized Balb/c mice to ovalbumin (OVA) with two intraperitoneal injections. After sensitization, the animals were exposed to cigarette smoke twice a day, 30 min per exposition, for 12 consecutive days. In order to drive the cell to the lungs, four aerosol challenges were performed every 48 h with the same allergen of sensitization. OVA sensitization and challenge developed pulmonary Th2 characteristic response with increased airway responsiveness, remodeling, increased levels of IgE, interleukin (IL)-4, and IL-13. Cigarette smoke, unexpectedly, reduced the levels of IL-4 and IL-13 and simultaneously decreased anti-inflammatory cytokines as IL-10 and transforming growth factor (TGF)-β in sensitized and challenged animals. OVA combined with cigarette smoke exposition decreased the number of eosinophils in bronchoalveolar lavage and increased the number of neutrophils in lung. The combination of cigarette smoke and lung allergy increased recruitment of lymphoid dendritic cells (DCs) into lymph nodes, which may be the leading cause to an increase in number and activation of CD8+ T cells in lungs. In addition, lung allergy and cigarette smoke exposure decreased an important regulatory subtype of DC such as plasmacytoid DC as well as its activation by expression of CD86, PDL2, and ICOSL, and it was sufficient to decrease T regs influx and anti-inflammatory cytokines release such as IL-10 and TGF-β but not enough to diminish the structural changes. In conclusion, we observed, in this model, that OVA sensitization and challenge combined with cigarette smoke exposure leads to mischaracterization of the Th2 response of asthma by decreasing the number of eosinophils, IL-4, and IL-13 and increasing number of neutrophils, which is related to the increased number of CD8ɑ+ DCs and CD8+ T cells as well as reduction of the regulatory cells and its released cytokines.

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Hippo/Mst signalling couples metabolic state and immune function of CD8?+ dendritic cells.

Publications

Hippo/Mst signalling couples metabolic state and immune function of CD8α<sup>+</sup> dendritic cells.

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