Lymphocyte-activation gene 3 receptor (LAG-3) (LAG-3)

Lymphocyte-activation gene 3 (LAG-3) is a type I transmembrane protein and a member of the immunoglobulin superfamily that serves as a critical inhibitory immune checkpoint receptor [1, 3, 4]. Primarily expressed on activated T cells, natural killer (NK) cells, and B cells, LAG-3 functions by binding to its primary ligand, MHC class II, as well as other ligands like FGL1, Galectin-3, and LSECtin, to negatively regulate T cell activation, proliferation, and cytokine production [2, 8, 9]. Structurally, LAG-3 is closely related to CD4 but binds MHC class II with significantly higher affinity, enabling it to effectively compete for binding and suppress immune responses [3, 9]. In the context of cancer, chronic antigen exposure leads to high LAG-3 expression, contributing to T cell exhaustion and allowing tumors to evade immune surveillance [4, 5, 16]. Therapeutic strategies targeting LAG-3, such as the FDA-approved monoclonal antibody relatlimab, aim to block these inhibitory signals and restore the anti-tumor activity of T cells, particularly when used in combination with PD-1/PD-L1 inhibitors [4, 6, 8]. Beyond oncology, LAG-3 is being investigated for its role in autoimmune disorders, chronic infections, and neurodegenerative diseases like Parkinson's, where its modulation could help restore immune balance or prevent pathological protein spreading [1, 2, 10].

Other names

CD223Lymphocyte activating 3LAG3LAG-3

LAG-3 functions as an inhibitory immune checkpoint by binding to its primary ligands, MHC class II and FGL1, which suppresses T-cell receptor (TCR) signaling and downstream activation [1, 8, 12]. This interaction leads to the disruption of the association between CD3 and LCK, preventing effective TCR signaling [8, 9]. Therapeutic antibodies block these interactions to prevent the delivery of inhibitory signals, thereby restoring T-cell proliferation, cytokine production, and cytotoxic activity against tumor cells [6, 13, 16].