Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - DENDRITIC CELLS (Identification and targeting of metabolic pathways in dendritic cells that regulate their immune polarizing function)

Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling activation and polarization of effector T helper cells (Th) and regulatory T cell responses (Treg). Therefore, there is a major focus on developing approaches to manipulate DC function for immunotherapy. It is well known that changes in cellular activation are coupled to profound changes in cellular metabolism. However, only recently, based on studies with T cells and macrophages, the picture is emerging that manipulation of cellular metabolism can be used to shape immune responses. This field of immunometabolism is rapidly evolving as one of the new frontiers in science. Nonetheless, still little is known about the metabolic processes that support DC activation or about the metabolic requirements for DCs to drive Th1, Th2 or Treg responses. My proposal aims to fill this gap and focuses on the novel concept that cellular metabolism regulates the immune-polarizing properties of DCs. Specifically I hypothesize that conditioning of DCs by bacterial products results in a shift to glycolytic metabolism to acquire a Th1-polarizing phenotype, whereas Th2-DCs and Tol-DCs will display a shift towards mitochondrial OXPHOS fueled by FAO, that these states of metabolism are required for optimal Th1 and Th2/Treg polarization by these DCs, respectively and that manipulation of these metabolic pathways can be used in therapeutic settings to improve DC-based vaccinations

The main objectives of this proposal are the following:
Key objective 1): Characterize the metabolic profiles of Th1-, Th2- and Treg- promoting DCs.
Key objective 2): Determine whether glycolytic and mitochondrial metabolism in DCs are required for their Th1 and Th2/Treg-polarizing capacity, respectively
Key objective 3): Determine if manipulation of glycolytic or mitochondrial metabolism in DCs can be used to improve efficacy of DC-based immunotherapy

To address objective 1, we have performed detailed metabolic and transcriptomic analyses of human monocyte derived DCs, that have been stimulated with Th1, Th17, Th2 and Treg polarizing compounds. Thus far this has resulted in the identification of specific metabolic pathways that are characteristic of different Th-cell polarizing DCs. Specifically we found that Th1 and Th17-promoting DCs have increased glycolytic metabolism, with little changes in oxidative metabolism. In contrast, we observed that Th2 polarizing-DCs have suppressed glycolytic metabolism and instead appear to have heightened oxidative phosphorylation fueled by fatty-acid oxidation. Interestingly, unbiased integration of metabolic and transcriptomic data identified the UDP-GlcNAc synthesis pathway as a key defining metabolic property of Th2-priming moDCS. Finally, preliminary experiments suggest that tolerogenic DCs are metabolically characterized by both increased glycolytic and mitochondrial metabolism.

We have made a start with addressing objective 2. This has yielded interesting preliminary data. Consistent with a the observation that glycolysis was increased in Th1-polarizing DCs, but suppressed in Th2-priming DCs, we found that inhibition of glycolysis alone was sufficient to condition DCs for Th2 polarization. Conversely we found that when Fatty acid oxidation was impaired in Th2-polarizing DCs, their ability to prime Th2 responses was compromised.

Key objective 3 has not yet been addressed but we will aim to do so the coming year.

Together, the findings until now show that DCs with different T cell polarizing properties have different metabolic characteristics and that these metabolic differences are functionally important as targeting or manipulation of these metabolic pathway change the ability of these cells to prime certain Th cell responses. Hence, given the striking effects of metabolic manipulation of DCs on their capacity to prime and polarize Th cell responses, we believe that the data generated by this project provides a convincing proof of concept that targeting metabolism of DCs can be highly promising as a novel approach to modulate immune responses and as such may contribute to the development of more efficacious types of immunotherapy in which DCs play a central role.

Reported by

ACADEMISCH ZIEKENHUIS LEIDEN - LEIDS UNIVERSITAIR MEDISCH CENTRUM
Netherlands

Subjects

Life Sciences
Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top