Fig. 3. The typical ligand of LAG-3 is MHC class II (MHC-II), which interacts stably with LAG-3 through the D1 domain and has a significantly higher affinity than CD4.

The high-affinity LAG-3Ig/MHC-II binding competes with CD4/MHC-II interaction to mediate the suppressed T cell proliferation and inhibitory immune response. The second ligand of LAG-3 is Gal-3, which has been found to be expressed in multiple cancer cells and activated T cells. Gal-3 can interact with LAG-3 and this binding is essential for the inhibitory cytotoxicity of CD8 + T lymphocytes. Other newly identified LAG-3 functional ligands include FGL1 and LSECtin. The blockade of LAG-3 with mAbs can relieve the T cell inhibitory immune response triggered by the interaction between LAG-3 and its ligands.