Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.
Lymphocyte activation gene (LAG)-3 (CD223) is a CD4-related activation-induced cell surface molecule that binds to MHC class II molecules with high affinity and negatively regulates T cell expansion and homeostasis. In this study, we show that LAG-3 inhibits CD4-dependent, but not CD4-independent, T cell function via its cytoplasmic domain. Although high affinity interaction with MHC class II molecules is essential for LAG-3 function, tailless LAG-3 does not compete with CD4 for ligand binding. A single lysine residue (K468) within a conserved "KIEELE" motif is essential for interaction with downstream signaling molecules. These data provide insight into the mechanism of action of this important T cell regulatory molecule.
Workman
Creg J
CJ
Department of Immunology, St. Jude Children's Research Hospital, 332 West Lauderdale, Memphis, TN 38105, USA.
Dugger
Kari J
KJ
Vignali
Dario A A
DA
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D015704:CD4 Antigens / Q000502:physiology; D017124:Conserved Sequence; D003593:Cytoplasm / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D014407:Tumor Cells, Cultured; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D008565:Membrane Proteins; D000093322:Lymphocyte Activation Gene 3 Protein