Lymphocyte activation gene-3 (LAG-3), also known as CD223, is a protein expressed by activated CD4+ and CD8+ T cells. This protein binds to major histocompatibility complex (MHC) class II molecules with significantly higher affinity than CD4, and is associated with the T-cell receptor complex at the cell surface. It is hypothesized that LAG-3 might act as an important negative competitor of CD4, to modulate T cell proliferation, function and homeostasis.

Both MHC class II and LAG-3 are strongly upregulated in inflammatory responses. In tumor tissues, LAG-3 has been detected in tumor infiltrating lymphocytes. Immunohistochemical analysis revealed LAG-3 expression was distributed on lymphocytes scattered in renal cell carcinoma, melanoma and lymphomas. They were also detected in the tumor stroma as well as in the peritumoral tissue. In melanoma, expression of MHC II has been associated with poor prognosis. Recently, a study demonstrated that LAG-3 can prevent MHC II-positive melanoma cells from undergoing Fas-mediated apoptosis and also activate MAPK/Erk and PI3K/Akt survival pathways, conferring melanoma resistance to apoptosis and progression. Proper molecular regulation of T cell activation is critical for control of T cell homeostasis.