Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3

J Immunol. 2002 Nov 15;169(10):5392-5. doi: 10.4049/jimmunol.169.10.5392.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antigens, CD*
  • CD4 Antigens / physiology
  • Conserved Sequence
  • Cytoplasm / immunology
  • Down-Regulation / immunology*
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Hybridomas
  • Ligands
  • Lymphocyte Activation / immunology*
  • Lymphocyte Activation Gene 3 Protein
  • Membrane Proteins / chemistry
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Tumor Cells, Cultured


  • Antigens, CD
  • CD4 Antigens
  • Histocompatibility Antigens Class II
  • Ligands
  • Membrane Proteins
  • Lymphocyte Activation Gene 3 Protein