Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223)

J Immunol. 2004 Dec 1;173(11):6806-12. doi: 10.4049/jimmunol.173.11.6806.


Lymphocyte activation gene-3 (LAG-3; CD223) is a CD4-related transmembrane protein that binds to MHC class II molecules. We have recently shown that LAG-3 is required for maximal regulatory T cell function, and that ectopic expression of LAG-3 is sufficient to confer regulatory activity. In this study we show that LAG-3 is cleaved within the D4 transmembrane domain connecting peptide into two fragments that remain membrane associated: a 54-kDa fragment that contains all the extracellular domains and oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa peptide that contains the transmembrane and cytoplasmic domains. This NH(2)-terminal fragment is subsequently released as soluble LAG-3 (sLAG-3), a process that is increased after T cell activation in vitro and in vivo, and is found in the sera of C57BL/6 and RAG-1(-/-) mice. Modulation of LAG-3 cleavage may contribute to the function of this key regulatory T cell protein.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / blood
  • Antigens, CD / chemistry*
  • Antigens, CD / genetics
  • CD4-Positive T-Lymphocytes / chemistry*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Humans
  • Hybridomas
  • Hydrolysis
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocyte Activation* / genetics
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / blood
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Structure, Tertiary
  • Spleen / chemistry
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism


  • Antigens, CD
  • Membrane Proteins
  • Peptide Fragments
  • Lymphocyte Activation Gene 3 Protein