Abstract
The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism.
Highlights
The concept that cellular metabolism controls the functions of immune cells has greatly evolved in the past few years, with T cells leading the way over other immune cell types [1, 2]
KBN B cells showed a similar Oxygen Consumption Rate (OCR) profile as KRN, but glycolysis was globally higher in KBN than KRN B cells, especially when mitochondrial ATP production was inhibited after oligomycin and FCCP treatment (Figure 1A)
To produce high levels of anti-glucose-6-phosphate isomerase (GPI) IgG, KBN arthritis strongly relies on the expansion of CD4+ follicular helper T (Tfh) cells and IL-21 they secrete, both which are required for the production of high-affinity class-switched antibodies [22]
Summary
The concept that cellular metabolism controls the functions of immune cells has greatly evolved in the past few years, with T cells leading the way over other immune cell types [1, 2]. Quiescent T cells produce ATP by oxidizing glucose, fatty acids or glutamine. A number of metabolic inhibitors block key nodes of T cell metabolism. 2-deoxyglusose (2DG) inhibits glucose metabolism at its first enzymatic steps. Metformin reduces mitochondrial respiration in activated T cells [3], which is consistent with its inhibition of the electron transport chain complex 1 [4]. Based on the drastic differences in metabolic requirements and the critical role of effector T cells in autoimmune diseases, T cell metabolism has been proposed as a target for immunotherapy [5, 6]. We and others have shown the existence of multiple immune metabolism defects in lupus patients and mouse models of the disease [7]. We have shown that the combination of 2DG and metformin
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