Energy Overload: ATP-P2X7-Mediated T Cell Activation in Obesity-Induced Type 2 Diabetes 9286

Abstract Description Obesity-induced type 2 diabetes (ObT2D) is increasingly recognized as a key driver of chronic inflammation, underscored by sustained T-cell activation. However, the link between this metabolic disorder and T-cell responses remains poorly understood. We propose that in ObT2D, excess extracellular ATP stimulates purinergic receptors on T cells, triggering metabolic shifting to fuel chronic inflammation. Mice fed with a high-fat diet (HFD) for 12 weeks to induce ObT2D. Compared with lean controls, the ObT2D mice exhibit markedly increased body weight, blood glucose, and serum ATP, alongside heightened T cell activity as examined by cytokine production. In vitro, ATP stimulation increased activation markers in primary CD8Ts, suggesting antigen-independent T-cell activation mediated by elevated extracellular ATP in ObT2D. Because T-cell activation requires significant energy, we investigated whether ATP-P2X7 signaling drives metabolic reprogramming in ObT2D T cells. Indeed, ATP-treated CD8Ts displayed enhanced glucose uptake and a marked increase in glycolysis compared with controls. To pinpoint the role of P2X7 in this metabolic shift, ongoing studies are using P2X7 knockout mice subjected to the same HFD regimen. Our study highlights a central role for ATP-P2X7-mediated signaling in T-cell activation and the associated chronic inflammation in ObT2D. Targeting P2X7 may offer a new therapeutic opportunity to mitigate unneeded immune responses and improve metabolic health in ObT2D. Funding Sources Sturgis Foundation Grant (UAMS Foundation intramural grant) (PI, Liu) 01/2024 – 12/2024 Diabetes Promotes Hypertension via Metabolic Reprogramming R01 HL146713-06 NIH/NHLBI (PI, Mu) 04/2019 – 03/2029 T Cell Homing to the Kidney Contributes to Salt Retention and Blood Pressure Regulation Topic Categories Immune Mechanisms of Human Disease (HUM)