Lag3, also known as CD223 (Lymphocyte activation gene-3), is an immune checkpoint receptor. It plays a crucial role in controlling excessive immune activation to prevent autoimmunity. LAG3 transmits inhibitory signals to T cells upon binding to ligands like MHC class II, FGL1, and the TCR-CD3 complex, leading to T-cell dysfunction. This regulation is of great biological importance, especially in the context of the tumor microenvironment, where its persistent expression contributes to T-cell exhaustion [1,2,3].

In Treg cell-specific Lag3-mutant mouse models, Lag3 was found to be essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells. Inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme, restored normal metabolism and suppressive function in these cells. This indicates that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming [4].

In conclusion, Lag3 is a significant immune checkpoint molecule involved in maintaining immune homeostasis, especially in preventing autoimmunity and in Treg cell-mediated immunosuppression. The Treg cell-specific Lag3-mutant mouse model has provided valuable insights into the role of Lag3 in regulating Treg cell function and autoimmunity, which may contribute to the development of immunotherapies for autoimmune diseases and cancer.