CD4+ T cells are a critical component of the adaptive immune system as they generate large amounts of cytokines that help shape the immune milieu. Additionally, they are the primary contributors to the immunopathology exhibited in Type 1 Diabetes. The field of immunometabolism has elucidated that the cellular metabolic profile of immune cells has a significant impact on their function, and ultimately the fate of the overall response. Naïve CD4+ T cells rely primarily on mitochondrial oxidative phosphorylation, but upon antigen encounter, reprogram their metabolism to aerobic glycolysis. Understanding the mechanisms that govern these programs could be critical in developing new therapies for limiting aberrant T cell responses in autoimmunity. Here we examined the contributions of two different molecules, Lymphocyte Activation Gene 3 (LAG-3) and reactive oxygen species (ROS) in controlling T cell metabolism. LAG-3 is an inhibitory receptor expressed on the surface of CD4+ T cells, and deficiency in naïve T cells leads to enhanced homeostatic expansion. Our results indicate that LAG-3 expression on naïve CD4+ T cells serves to restrain cellular metabolism and mitochondrial biogenesis as a means of maintaining quiescence. These results are compelling as loss of LAG-3 expression in a model of Type 1 Diabetes results in accelerated disease progression, potentially due to T cell metabolic enhancements, as our data would suggest. Single nucleotide polymorphisms in the LAG-3 gene have also been linked to autoimmune disease susceptibility. With regards to ROS, Type 1 Diabetes is known to be highly driven by oxidative stress, and CD4+ T cells require acute doses of ROS to drive optimal activation. Therefore, we sought to understand if ROS signaling contributes to the metabolic transition that occurs during T cell activation. Indeed, ROS inhibition resulted in reduced mTOR signaling and aerobic glycolysis. Altering metabolism in this manner also delayed Type 1 Diabetes progression in an adoptive transfer model of disease. Collectively, this work demonstrates that both LAG-3 and ROS regulate CD4+ T cell metabolism, which, in turn, greatly impacts T cell activation potential and ability to drive disease
