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. 2018 May;9(5-6):176–189. doi: 10.18632/genesandcancer.180

Figure 2. LAG-3 signaling and the interplay with other immune checkpoints.

Figure 2

The interaction of LAG-3 with MHC-II prohibits the binding of the same MHC molecule to a TCR and CD4, thus suppressing TCR signal. LAG-3 transmits an inhibitory signal via the KIEELE motif in the cytoplasmic tail. Crosslinking of LAG-3 and CD3/TCR complex can impair T cell proliferation, cytokines secretion, and calcium ion fluxes. LAG-3 also interacts with two novel ligands postulated, Gal-3 and LSECtin, expressed on melanoma cells to modulate CD8+ T-cell function within the TME. Strikingly, LAG-3 inhibits T-cell activation collectively with other immune checkpoints, especially PD-1. Antagonist antibodies targeting inhibitory immune checkpoints can restore T-cell function and have shown benefits in active clinical trials. Abbreviations: APCs = antigen presenting cells; MHC = major histocompatibility complex; TCR = T-cell receptor; PD-1 = programmed death 1; PD-L1 = programmed cell death ligand-1; LAG-3 = lymphocyte activation gene-3; CTLA-4 = cytotoxic T-lymphocyte antigen-4; Gal-3 = Galectin-3; LSECtin = Liver sinusoidal endothelial cell lectin.