Low-dose 2-Deoxy Glucose Stabilises Tolerogenic Dendritic Cells and Generates Potent in vivo Immunosuppressive Effects

Maria Christofi, S. Le Sommer, Christine Moelzer* (Corresponding Author), I. P. Klaska, L Kuffova, J V Forrester* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
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Cell therapies for autoimmune diseases using tolerogenic dendritic cells (tolDC) have been promisingly explored. A major stumbling block has been generating stable tolDC, with low risk of converting to mature immunogenic DC (mDC), exacerbating disease. mDC induction involves a metabolic shift to lactate production from oxidative phosphorylation (OXPHOS) and β-oxidation, the homeostatic energy source for resting DC. Inhibition of glycolysis through the administration of 2-deoxy glucose (2-DG) has been shown to prevent autoimmune disease experimentally but is not clinically feasible. We show here that treatment of mouse bone marrow-derived tolDC ex vivo with low-dose 2-DG (2.5 mM) (2-DGtolDC) induces a stable tolerogenic phenotype demonstrated by their failure to engage lactate production when challenged with mycobacterial antigen (Mtb). ~ 15% of 2-DGtolDC express low levels of MHC class II and 30% express CD86, while they are negative for CD40. 2-DGtolDC also express increased immune checkpoint molecules PDL-1 and SIRP-1α. Antigen-specific T cell proliferation is reduced in response to 2-DGtolDC in vitro. Mtb-stimulated 2-DGtolDC do not engage aerobic glycolysis but respond to challenge via increased OXPHOS. They also have decreased levels of p65 phosphorylation, with increased phosphorylation of the non-canonical p100 pathway. A stable tolDC phenotype is associated with sustained SIRP-1α phosphorylation and p85-AKT and PI3K signalling inhibition. Further, 2-DGtolDC preferentially secrete IL-10 rather than IL-12 upon Mtb-stimulation. Importantly, a single subcutaneous administration of 2-DGtolDC prevented experimental autoimmune uveoretinitis (EAU) in vivo. Inhibiting glycolysis of autologous tolDC prior to transfer may be a useful approach to providing stable tolDC therapy for autoimmune/immune-mediated diseases.

Original languageEnglish
Pages (from-to)2857-2876
Number of pages20
JournalCellular and Molecular Life Sciences
Issue number6
Early online date19 Oct 2020
Publication statusPublished - Mar 2021

Bibliographical note

Open Access via Springer Compact Agreement
University of Aberdeen Development Trust Grant number RG14251, RG12663
We thank the University of Aberdeen Iain Fraser Flow Cytometry core facility, and the University of Aberdeen Histology and Microscopy core facility for processing of histology slides. The authors thank University of Aberdeen Medical Research Facility for technical assistance with in vivo experiments. We thank Dr. Tian Yu, Dr. Yi-Hsia Liu, Mrs Rosemary Fordyce, and Mrs Elizabeth Muckersie for technical assistance with in vivo and in vitro experiments.
This work was supported by funds from the University of Aberdeen Development Trust Grants RG14251 and RG12663. Maria Christof was the recipient of a University of Aberdeen PhD Studentship. Samantha Le Sommer was funded by a Wellcome Trust ISSF Postdoctoral Fellowship.


  • Autoimmunity
  • Cell therapy
  • Metabolic programming
  • Tolerance
  • Zbtb46


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