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Interleukin-35-Producing CD8?⁺ Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.

ABSTRACT: Dendritic cells (DCs) play a central role in shaping immunogenic as well as tolerogenic adaptive immune responses and thereby dictate the outcome of adaptive immunity. Here, we report the generation of a CD8?⁺ DC line constitutively secreting the tolerogenic cytokine interleukin (IL)-35. IL-35 secretion led to impaired CD4⁺ and CD8⁺ T lymphocyte proliferation and interfered with their function in vitro and also in vivo. IL-35 was furthermore found to induce a tolerogenic phenotype on CD8?⁺ DCs, characterized by the upregulation of CD11b, downregulation of MHC class II, a reduced costimulatory potential as well as production of the immunomodulatory molecule IL-10. Vaccination of mice with IL-35-expressing DCs promoted tumor growth and reduced the severity of autoimmune encephalitis not only in a preventive but also after induction of encephalitogenic T cells. The reduction in experimental autoimmune encephalitis severity was significantly more pronounced when antigen-pulsed IL-35⁺ DCs were used. These findings suggest a new, indirect effector mechanism by which IL-35-responding antigen-presenting cells contribute to immune tolerance. Furthermore, IL-35-transfected DCs may be a promising approach for immunotherapy in the context of autoimmune diseases.

SUBMITTER: Haller S

PROVIDER: S-EPMC5296329 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Interleukin-35-Producing CD8α+ Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.

Haller Sergio S Duval Anaïs A Migliorini Romain R Stevanin Mathias M Mack Vanessa V Acha-Orbea Hans H

Frontiers in immunology 20170208

Dendritic cells (DCs) play a central role in shaping immunogenic as well as tolerogenic adaptive immune responses and thereby dictate the outcome of adaptive immunity. Here, we report the generation of a CD8α+ DC line constitutively secreting the tolerogenic cytokine interleukin (IL)-35. IL-35 secretion led to impaired CD4+ and CD8+ T lymphocyte proliferation and interfered with their function in vitro and also in vivo. IL-35 was furthermore found t ...[more]

PMID: 28228759

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Project description: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 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.

Dataset Information

Interleukin-35-Producing CD8?⁺ Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.

Publications

Interleukin-35-Producing CD8α<sup>+</sup> Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.

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Dataset Information

Interleukin-35-Producing CD8?+ Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.

Publications

Interleukin-35-Producing CD8α<sup>+</sup> Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Interleukin-35-Producing CD8?⁺ Dendritic Cells Acquire a Tolerogenic State and Regulate T Cell Function.