Lymphocyte activation gene 3 (LAG-3) regulates activation-induced CD4+ T cell metabolic transition (IRM6P.725)

LAG-3 negatively regulates CD4+ T cell proliferation and effector function by competing with CD4 for MHC class II binding. Others have demonstrated that loss of LAG-3 results in CD4+ T cell hyperresponsiveness and accelerated autoimmunity, further supporting LAG-3’s regulatory capabilities. In order for optimal CD4+ T cell activation, naive T cells must transition their metabolic program from oxidative phosphorylation (OXPHOS) to aerobic glycolysis (AG), a faster process that drives macromolecule production. We hypothesized that LAG-3 regulates the metabolic transition of CD4+ T cells from OXPHOS to AG, and in turn, loss of LAG-3 expression results in a faster transition to AG, promoting T cell hyperproliferation. At baseline, B6.LAG-3-/- splenocytes exhibited enhanced spare respiratory capacity as compared to WT controls, which correlated with increased mitochondrial mass and expression of the mitochondrial biogenesis transcription factor TFAM (2-fold), and mitochondrial complexes I-IV. Upon suboptimal Con A stimulation, LAG-3-/- splenocytes demonstrated greater upregulation of glycolysis-associated genes by 24 hrs (1.5 - 3 fold). These results correlated with increased Myc expression and mTOR signaling, both of which are crucial for driving AG. Taken together, these data indicate that LAG-3 regulates CD4+ T cell activation by controlling metabolic programing since the loss of LAG-3 results in a more metabolically primed phenotype.