LAG-3 (also called CD223) is a high affinity MHC class II ligand present on the surface of CD4+CD8+ T cells and NK cell, with shared homology in structure to CD4 molecules. It has a glutamic acid-proline (EP) repetitive sequence found in other functionally distinct mammalian, parasitic, and bacterial proteins that may influence a conserved biological function. LAG-3+CD4+CD8+ T cells can associate with the T cell receptor (TCR) and downregulate TCR signaling in vitro. LAG-3 inhibits CD4-dependent T cell function via its cytoplasmic domain. LAG-3 Lys-468 within a conserved KIEELE motif is essential for interaction with downstream signaling molecules. Furthermore, as a checkpoint inhibitor target, it may be superior to CTLA-4 and PD-1 since both antibodies only activate effector T-cells, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity.
