Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice

Abstract

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction.A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and also restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies. Significance StatementFine tuning of the immune response is critical to health. This fine tuning is lost in autoimmunity and cancer and must be restored to prevent undesirable outcomes. Immune cell metabolism can regulate the immune response but to date chronic interventions have been needed to produce any biologic effect. Our study in lupus-prone animals demonstrates that disease-associated changes in immune cell metabolism create a barrier to immune tolerance, which can be reset by short term metabolic treatment with 2-deoxyglucose and metformin. Metabolic therapy restored normal expression of extracellular receptors, which was required for successful immune therapy.These findings reveal the role of glycoregulation in the immune response and indicate an important interaction between immune metabolism and responsiveness to immune therapy. the spleen (Figure 1 B&C) (33). Anti-CD45RB treatment leads to a B cell dependent expansion of CD4+ Foxp3+ Tregs to promote longterm tolerance induction (23,32). We hypothesized that this B cell mobilization would expand CD4+ Foxp3+ Tregs in both SLE123 and B6 mice. Analysis of the Foxp3 + and CD25 + fractions of the CD4 + population revealed expansion of Tregs in both B6 and SLE123 mice following anti-CD45RB therapy (Figure 1 D&E). Anti-CD45RB uncovers inappropriate effector responses to tolerogenic signaling.While expansion of Tregs is important for long-term tolerance in anti-CD45RB treatment, the effector compartment must also be temporarily modulated to facilitate adequate regulation (34,35). In healthy B6 mice, anti-CD45RB inhibits the Germinal Center (GC) response and temporarily cripples antibody production (28,35). In clinical SLE and in the mouse model of disease, there is an expansion of T-follicular helper (Tfh) cells and GC B cells that collaborate to generate autoantibodies that occlude and damage the nephron...

Oxidative Stress Contributes to Inflammatory and Cellular Damage in Systemic Lupus Erythematosus: Cellular Markers and Molecular Mechanism

“… 38 Glycolytic activity was found to be comparatively higher in transgenic mice that yielded lupus-like antibodies compared to controls. 39 Since SLE patients had high BAFF levels, their glycolysis status might appear noticeably higher than the controls, which warrants more definitive investigation. Depressed lipid oxidation in B cells of SLE patients is a potential consequence of the condition that the lupus allele potentiates the expression of the metabolic gene encoding the protein fatty acid amide hydrolase (FAAH), whose level is explicitly raised in plasma cells.…”

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

“…The simultaneous administration of the mitochondrial metabolism inhibitor metformin and glycolysis inhibitor 2-DG significantly restored immune tolerance of lupus mice, dampening autoimmune inflammation. These findings indicate that immunometabolic regulation may be a practical strategy for SLE therapy (125).…”

Glucose metabolism and glycosylation link the gut microbiota to autoimmune diseases

“…Diet regulation: a helpful and safe intervention to guide the establishment of healthy gut microbiome Lupus-prone mice, multiple sclerosis complex as well as the restored tolerance to allografts in lupusprone mice, probably via targeting glycolysis and oxidative phosphorylation (184).…”

“…Glycoregulation therapy with 2-DG and metformin changes the T cell surface glycosylation patterns and enables immune tolerance induction as evidenced by the reduced anti-dsDNA antibody titers and the decreased renal deposition of immune complex as well as the restored tolerance to allografts in lupus-prone mice, probably via targeting glycolysis and oxidative phosphorylation ( 184 ).…”