LAG-3, full name lymphocyte activation gene-3, plays a vital role in regulating T cell activation, proliferation, and homeostasis. Inhibiting LAG-3 allows T cells to regain cytotoxic activity, reduce the suppressive function of regulatory T cells, and enhance the killing effect on tumors.
Major histocompatibility complex class II transactivator (CIITA) has been identified as a key regulatory factor for LAG-3 ligand. CIITA not only induces MHCII expression but also induces expression of MHCII accessory molecules, including CD74 and H2-DM. The accessory molecules of MHCII help in the formation of peptide-MHCII complexes (pMHCII) and cell surface presentation, showing stable structural conformation in the conventional antigen presentation pathway. LAG-3 distinguishes the conformation of pMHCII and selectively binds with stable pMHCII. Therefore, LAG-3 preferentially inhibits the activation of CD4+ T cells recognizing stable pMHCII. Additionally, it has been demonstrated that LAG-3 does not compete with CD4 for binding pMHCII. Instead, LAG-3 inhibits T cell activation by delivering inhibitory signals through intracellular domains.
Similar to PD-1 and CTLA-4, LAG-3 is not expressed on naïve T cells but can be induced upon antigen stimulation on CD4+ and CD8+ T cells. Since the inhibitory function of LAG-3 is closely related to its expression level on the cell surface, the regulation of LAG-3 expression is crucial. Prolonged exposure to antigens caused by chronic viral, bacterial, or parasitic infections leads to sustained high levels of LAG-3 and other inhibitory co-receptors expression on CD4+ and CD8+ T cells. These T cells lose potent effector functions, termed as exhausted T cells. LAG-3 blockade has been shown to restore vitality to exhausted T cells and enhance anti-infection immunity, although its effect is smaller compared to PD-1 blockade.
