Targeting T cell Metabolism to Combat Autoimmunity: Implications for the Future of Type 1 Diabetes Therapeutics

Abstract

Advances in the field of immunometabolism have indicated that cellular metabolic programs control T cell differentiation and effector functions. As CD4+ T cells are significant contributors to destruction of the insulin-secreting β cell in Type 1 Diabetes (T1D), strategies to limit autoreactive T cell activation and promote durable tolerance have been explored in an effort to prevent or delay disease onset. Interestingly, substantial evidence indicates that autoreactive T cells are at a heightened activation status associated with dysregulation of metabolic pathways, with distinct nutrient preferences and needs of their own. While largely unexplored in T1D, specific metabolic pathways have been exploited to correct known defects in several autoimmune diseases including but not limited to Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). These therapeutic strategies have been focused on targeting glycolysis, which is the major pathway used by activated T cells as it is required for acquisition of effector functions. Use of glycolysis inhibitors such as 2-Deoxy-D-glucose (2-DG), have shown impressive success in limiting T cell mediated damage that could prevent or reverse onset of autoimmunity. More importantly, while specificity has been a major hurdle for use of immunotherapies, regulating immunity by targeting metabolism resulted in selective targeting of autoreactive T cells while leaving global immune function intact, a phenomenon commonly referred to as “cellular selectivity based on demand”. This review will outline examples of metabolic regulation success in autoimmunity and provide evidence to support use of these inhibitors in T1D, where new therapeutic strategies are desperately needed.