LAG-3 is a CD4 homolog type I membrane protein with four extracellular Ig superfamily domains. Similar to CD4, LAG-3 oligomerizes at the surfaces of T cells and binds to MHC II on APCs but with significantly higher affinity than CD4. LAG-3 is expressed on activated CD4+ and CD8+ T lymphocytes where it associates with the CD3–TCR complex at the cell surface and negatively regulates signal transduction. As a consequence, it negatively regulates T cell proliferation, function, and homeostasis. Indeed, the role of LAG-3 in the downregulation of T cell responses is quite recognized. There is also increasing evidence of its involvement in regulatory function of tumor-infiltrated T cells in cancer, such as in Hodgkin's lymphomas and in prostate cancer. Recently, LAG-3 expression also defined an active CD4+CD25highFOXP3+ Treg subset, which is endowed with potent suppressor activity that requires cell-to-cell contact and is found at enhanced frequency in PBMCs of patients with melanoma and is expanded at tumor sites. As a soluble fusion protein, LAG-3 has also been shown to bind MHC II with a much higher avidity than CD4, to increase the capacity of MHC II-positive macrophages and immature dendritic cells to induce T cell responses in vitro, and to enhance the in vitro induction of viral and tumor-specific cytotoxic T cells. Accordingly, the LAG-3 fusion protein has been suggested as a potential adjuvant for cancer vaccines, including those for melanoma, for which most attempts at immunotherapy have met with little clinical success.
Hemon P, Jean-Louis F, Ramgolam K, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis[J]. The Journal of Immunology, 2011, 186(9): 5173-5183.