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Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice
Christopher S. Wilson, … , Amy S. Major, Daniel J. Moore
Christopher S. Wilson, … , Amy S. Major, Daniel J. Moore
Published August 17, 2021
Citation Information: JCI Insight. 2021;6(19):e143245. https://doi.org/10.1172/jci.insight.143245.
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Research Article Transplantation

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

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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 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.

Authors

Christopher S. Wilson, Blair T. Stocks, Emilee M. Hoopes, Jillian P. Rhoads, Kelsey L. McNew, Amy S. Major, Daniel J. Moore

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Figure 1

Tolerance-inducing anti-CD45RB mobilizes regulation in both the B and T lymphocyte compartments in B6 and SLE123 mice.

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Tolerance-inducing anti-CD45RB mobilizes regulation in both the B and T ...
(A) A 7-day course of aCD45RB was administered to B6 and SLE123 mice. Flow cytometry analysis of B6 and SLE123 mice (n = 4 per group, 9- to 10-week-old females) demonstrated a slight reduction in splenic B cells in both strains. (B) Subset analysis of the B cell compartment in these mice revealed a reduction in the marginal zone (MZ) while the Follicular (FO) and Transitional (Tr.) did not show substantial changes. (C) A cartoon diagram demonstrates the flow cytometry subsetting strategy, with quantification at right. Analyzed using a 1-way ANOVA followed by Tukey’s multiple comparison test. (D and E) Flow cytometry analysis showed B6 mice experienced an expansion of CD4+CD25+Foxp3+ Tregs when treated with aCD4RB (top panel). The SLE123 mice experienced a similar increase in the cells (bottom panel). This increase is quantified in E. Analyzed using a 1-way ANOVA followed by Tukey’s multiple comparison test. Analysis was carried out in 9- to 12-week-old female mice, n = 5 per group.

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