LAG-3 (Lymphocyte activation gene-3; CD223) is a transmembrane protein that binds to MHC class II molecules and negatively regulates T cell receptor signaling. It is expressed on activated T cells, NK cells, and plasmacytoid dendritic cells (pDC). LAG-3 limits the expansion of activated T cells and pDC in response to select stimuli. Proteolytic shedding of LAG-3 enables normal T cell activation by removing the negative regulation. Binding of a homodimerized soluble LAG-3/Ig fusion protein to MHC class II molecules induces maturation of immature DC as well as secretion of pro-inflammatory cytokines by cytotoxic CD8+ T cells and NK cells.