Background/Purpose: Cellular metabolism controls T cell functions, with TCR-mediated activation enhancing metabolism, and substrate utilization modulating effector functions.  Autoreactive CD4 T cells are key effectors in lupus by providing help to B cells to produce high-affinity class-switched autoantibodies. We have previously shown that CD4 T cells from B6.Sle1.Sle2.Sle3 (TC) and BWF1 lupus-prone mice, as well as from lupus patients, have an elevated mitochondrial oxidation (OXPHOS) and glycolysis. A combination of metformin and 2DG, two metabolic inhibitors which target OXPHOS and glucose metabolism, respectively, normalized the cellular metabolism of these T cells in vitro, and in vivotreatments reversed all disease phenotypes in TC and BWF1 mice. These two models are genetically related and their T cells are characterized by a high production of IFNγ. In this study, we investigated the efficacy of metabolic inhibitors in BXSB.Yaa mice, an unrelated model driven by type I Interferons.

Methods: Two month old TC or BXSB.Yaa mice were treated with yhree single metabolic inhibitors for 8 weeks (N = 10-22): metformin, 2DG, or dichloroacetate (DCA, an inhibitor of glycolysis) and compared to untreated controls (N = 27). T cell glycolysis and OXPHOS were measured with an extracellular fluid analyzer. Lymphocyte activation and effector subset distribution were measured by flow cytometry. Disease progression was assessed by ELISA and ANA staining for autoantibodies and histology for renal pathology.  CD4 T cells from lupus mice and controls were polarized under Th1 conditions in the presence of metformin, 2DG, or DCA, and IFNγ production was measured by flow cytometry.

Results: CD4 T cells from BXSB.Yaa mice have a significantly higher glycolysis and OXPHOS than control mice. However, OXPHOS was significantly lower in BXSB.Yaa than in TC CD4 T cells, indicating a lower contribution of OXPHOS to BXSB.Yaa T cell metabolism. All 3 metabolic inhibitors significantly reduced renal pathology, the most effective being 2DG in both strains. DCA was more effective that metformin in BXSB.Yaa mice while the reverse was true in TC mice. All 3 metabolic inhibitors also reduced lymphoid expansion and T cell activation, with again 2DG having the greatest effect. 2DG and metformin, but not DCA prevented autoantibody production in TC mice.  BXSB.Yaa autoantibody results are pending. In vitro Th1-polarized BXSB.Yaa CD4 T cells produced significantly more IFNγ than BXSB controls, but significantly less than TC CD4 T cells. Both 2DG and metformin decreased IFNγ production from polarized cells, but DCA, which increases pyruvate oxidation, also increased IFNγ production. This is consistent with their reduced OXPHOS, which supports which IFNγ production.

Conclusion: These results showed that inhibitors of glucose metabolism are effective in murine models in which lupus arise from different etiology. They suggest however that targeting mitochondrial oxidation may have better outcomes in IFNγ-driven disease while targeting glycolysis may be more effective type I IFN-driven disease. Further investigation of these models will lead to tailored pre-clinical models that target T cell metabolism for lupus treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-targeting-of-cd4-t-cell-metabolism-in-murine-models-of-lupus/