Low-dose 2-deoxy glucose stabilises tolerogenic dendritic cells and generates potent in vivo immunosuppressive effects
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Low‑dose 2‑deoxy glucose stabilises tolerogenic dendritic cells and generates potent in vivo immunosuppressive effects M. Christofi1 · S. Le Sommer1 · C. Mölzer1 · I. P. Klaska1 · L. Kuffova1,2 · J. V. Forrester1,3,4 Received: 9 April 2020 / Revised: 4 September 2020 / Accepted: 5 October 2020 © The Author(s) 2020
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. Keywords Cell therapy · Tolerance · Zbtb46 · Autoimmunity · Metabolic programming
Introduction
M. Christofi and S. Le Sommer contributed equally to this manuscript. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03672-y) contains supplementary material, which is available to authorized users.
Dendritic cells [1] are a diverse, heterogeneous group of specialist immune cells that are the immune system’s primary professional antigen-presenting cells. Recent studies [2, 3] have described the various differentiation pathways of bone marrow progenitor DC from the time they enter the circulation as immature precursors (pre-DC) to when they populate the tissues as tissue-resident DC, and/or migrate to secondary lymphoid organs in a CCR7-dependent manner.
* C. Mölzer chris
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