Identifying the Mechanisms by which Metformin Regulates CD8+ T Cell Oxidative Metabolism

Obesity drives chronic inflammation and reduces anti-viral immunity, in part due to T cell dysfunction. Obesity-associated T cell dysfunction has been linked to altered cellular metabolism characterized by increased glucose uptake and increased mitochondrial oxidation. We determined the effects of the metabolic drug metformin on oxidative metabolism in CD8+ T cells. We discovered that treatment of CD8+ T cells with metformin led to a rapid reduction in oxidative metabolism, a decrease in mitochondrial membrane potential, and reduced production of reactive oxygen species. Preliminary findings showed that CD8+ T cells from adenosine receptor knockout mice exhibited increased oxidative metabolism when treated with metformin, compared to CD8+ T cells from wild-type mice. In addition, we found an increase in phosphorylated AMPK and associated downstream signaling proteins following metformin treatment. Further investigation of this mechanism may lead to insights regarding the use of metformin to enhance immune responses to viral infections.