Lymphocyte Activation Gene-3 Maintains Mitochondrial and Metabolic Quiescence in Naive CD4⁺ T Cells

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed by CD4⁺ T cells and tempers their homeostatic expansion. Because CD4⁺ T cell proliferation is tightly coupled to bioenergetics, we investigate the role of LAG-3 in modulating naive CD4⁺ T cell metabolism. LAG-3 deficiency enhances the metabolic profile of naive CD4⁺ T cells by elevating levels of mitochondrial biogenesis. In vivo, LAG-3 blockade partially restores expansion and the metabolic phenotype of wild-type CD4⁺ T cells to levels of Lag3^-/- CD4⁺ T cells, solidifying that LAG-3 controls these processes. Lag3^-/- CD4⁺ T cells also demonstrate greater signal transducer and activator of transcription 5 (STAT5) activation, enabling resistance to interleukin-7 (IL-7) deprivation. These results implicate this pathway as a target of LAG-3-mediated inhibition. Additionally, enhancement of STAT5 activation, as a result of LAG-3 deficiency, contributes to greater activation potential in these cells. These results identify an additional mode of regulation elicited by LAG-3 in controlling CD4⁺ T cell responses.