T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding

Eur J Immunol. 1996 May;26(5):1180-6. doi: 10.1002/eji.1830260533.


T cell response to its antigen requires recognition by the T cell receptor together with a co-receptor molecule, either CD4 or CD8. Additional molecules have been identified that are capable of delivering the co-stimulatory signals provided by APC. Following T cell priming, a number of T cell activation antigens are expressed that may play a role in the inactivation phase of the T cell response. The lymphocyte activation gene (LAG)-3 protein and its counter-receptors, the major histocompatibility complex (MHC) class II molecules, are such activation antigens whose interaction may result in the down-regulation of the ongoing immune response. To investigate the role of LAG-3/class II molecule interaction, we produced a soluble form of LAG-3 by fusing the extracellular Ig domains of this membrane protein to the constant region of human IgG1 (LAG-3Ig). Here, we show a direct and specific binding of LAG-3Ig to class II molecules on the cell surface. In addition, we show that LAG-3/class II molecule interaction leads to the down-regulation of CD4+ Ag-specific T cell clone proliferation and cytokine secretion. This inhibitory effect is observed at the level of the effector cells and not the APC and is also found with anti-CD3 mAb, PHA + PMA or low-dose IL-2 driven stimulation in the absence of APC. These functional studies indicate that T cell MHC class II molecules down-regulate T cell proliferation following LAG-3 binding and suggest a role for LAG-3 in the control of the CD4+ T cell response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD*
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Clone Cells
  • Down-Regulation / immunology*
  • Genetic Vectors / immunology
  • Histocompatibility Antigens Class II / physiology*
  • Humans
  • Immunoglobulin G / chemistry
  • Immunoglobulin G / genetics
  • Lymphocyte Activation
  • Lymphocyte Activation Gene 3 Protein
  • Membrane Proteins / chemistry*
  • Membrane Proteins / immunology
  • Molecular Sequence Data
  • Protein Binding / immunology
  • Recombinant Fusion Proteins / pharmacology


  • Antigens, CD
  • Histocompatibility Antigens Class II
  • Immunoglobulin G
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human
  • soluble LAG-3 protein, human