The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells

Eur J Immunol. 2003 Apr;33(4):970-9. doi: 10.1002/eji.200323382.


The lymphocyte activation gene-3 (LAG-3, CD223) is a CD4-related, activation-induced cell surface molecule that binds to MHC class II with high affinity. The function of murine LAG-3 on T cells is unclear. Here, we show that V beta 7/8(+)LAG-3(-/-) T cells expand poorly following staphylococcal enterotoxin B (SEB) stimulation in vitro. LAG-3(-/-) T cells proliferate at a normal rate, but exhibit increased cell death. Similar observations were made with LAG-3(-/-)CD4(+)OT-II TCR transgenic T cells following peptide stimulation. Despite reduced T cell expansion and increased cell death, LAG-3(-/-)OT-II(+) T cells secrete more IL-2 and IFN-gamma following stimulation. Antigen-driven expansion of LAG-3(-/-) T cells was restored by constitutive expression of LAG-3 via retroviral-mediated stem cell gene transfer. We further show that LAG-3 function is mediated via its cytoplasmic domain, for which a conserved 'KIEELE' motif is essential. Our data support a role for LAG-3 in regulating the expansion of activated T cells.

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 / chemistry
  • Cell Death
  • Enterotoxins / pharmacology
  • Genes, T-Cell Receptor
  • Humans
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocyte Activation*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Sequence Alignment
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*


  • Antigens, CD
  • CD4 Antigens
  • Enterotoxins
  • Membrane Proteins
  • enterotoxin B, staphylococcal
  • Lymphocyte Activation Gene 3 Protein