LAG-3 (Lymphocyte activation gene-3), also known as CD223, is a member of the immunoglobulin superfamily (IgSF). The mature LAG-3 protein is a 496 amino acid (aa) membrane protein with a 421 aa extracellular region that contains four IgSF domains, a 21 aa transmembrane region and a 54 aa cytoplasmic region. LAG-3 and CD4 molecules share < 20% aa sequence homology but have a similar structure. Both molecules bind to MHC class II. LAG-3 binds to MHC class II with higher affinity than CD4. Both LAG-3 and CD4 genes are located on the distal part of the short arm of chromosome 12.