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

1 Citation (Scopus)

Abstract

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
Volume78
Issue number6
Early online date19 Oct 2020
DOIs
Publication statusPublished - Mar 2021

Keywords

  • Autoimmunity
  • Cell therapy
  • Metabolic programming
  • Tolerance
  • Zbtb46
  • RHEUMATOID-ARTHRITIS
  • ACTIVATION
  • HOMEOSTASIS
  • MACROPHAGE
  • EXPERIMENTAL AUTOIMMUNE UVEORETINITIS
  • SIRP-ALPHA
  • INHIBITION
  • IMMUNOTHERAPY
  • STEADY-STATE
  • T-CELLS

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