Following activation it is necessary for a subset
Following activation, it is necessary for a subset of activated effector T cells to survive as long-lived memory T cells. Metabolically, this transition is dependent upon the ability of the cell to downregulate aerobic glycolysis and transition back to a more oxidative phenotype. In fact, enhancement of OXPHOS via treatment with Metformin, an AMPK activator, has been shown to increase the frequency of memory T cells following activation (Sukumar et al., 2013). Because Lag3-deficient effector T cells are more glycolytic than WT cells, we would hypothesize that they would have a more difficult time transitioning back to OXPHOS, thus limiting the potential for generating memory T cells. Further studies would be necessary to more fully assess a role for LAG-3 in memory T cell generation. As mentioned earlier, LAG-3 has been described as a surface marker and mode of suppression for CD4+ regulatory T cells (Tregs) (Huang et al., 2004, Vignali et al., 2008). Studies examining the metabolic profile of Treg cells have indicated that like naive and memory subsets, they rely predominantly on OXPHOS. Specifically, Tregs utilize fatty suramin oxidation, driven by high levels of AMPK expression (Michalek et al., 2011). Work from Huang et al. (2004) indicated that Lag3 Tregs proliferated to a greater extent than WT Tregs, which is in line with our work and other previous work that LAG-3 expression inhibits T cell proliferation (Workman and Vignali, 2005). Our studies would further suggest that Lag3-deficient Tregs may demonstrate increased mitochondrial mass and metabolism, as a means of supporting increased proliferation. This could prove advantageous in autoimmunity as a means of increasing the Treg-to-T effector ratio, potentially providing better protection. However, it would be important to also verify that bioenergetic differences caused by LAG-3 loss do not interfere with suppressive capabilities, especially if regulation is LAG-3 dependent. Future studies are necessary to elucidate potential metabolic implications related to LAG-3 expression and Tregs. In the context of autoimmunity, LAG-3 has been shown to play a critical role in suppressing CD4+ T cell function. Global knockout and antibody blockade of LAG-3 in non-obese diabetic (NOD) animals accelerated type 1 diabetes (T1D) (Bettini et al., 2011, Okazaki et al., 2011). Moreover, animals with genetic Lag3 alterations that resulted in accelerated T1D had equally functional Treg populations, indicating that this disease progression was not due to dysfunctional Treg-mediated tolerance (Okazaki et al., 2011). Our data imply that the increased T1D progression in NOD.Lag3 animals may be due, in part, to the metabolic enhancement of diabetogenic CD4+ T cells, conferring greater activation and disease-inducing potential. Also, this metabolic advantage may enable resistance of Lag3 CD4+ effector T cells to Treg-mediated suppression, which has been described in other models (Durham et al., 2014). Human studies have been conducted to identify single nucleotide polymorphisms (SNPs) in genes that are associated with susceptibility to autoimmune diseases. A study by Zhang et al. (2005) identified SNPs in both the genes encoding Lag3 and Il-7r that are more highly associated with progression to multiple sclerosis. This work strengthens our conclusion that an inherent link exists between LAG-3 and IL-7R expression and signaling, which could contribute to the aberrant T cell responses in autoimmunity. Based on these studies and our work, future studies of human autoimmune-associated T cells with Lag3 mutations may indicate metabolic alterations that could contribute to pathogenicity. In summary, we have demonstrated a role for LAG-3 in the regulation of CD4+ T cell metabolism, which can thereby influence T cell homeostasis and activation. These findings have important implications for our understanding of T cell biology in many models, including autoimmunity and tumor immunology.