T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding.
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.
Huard
B
B
Laboratoire d'Immunologie Cellulaire, INSERM U333, Institut Gustave-Roussy, Villejuif, France.
Prigent
P
P
Pagès
F
F
Bruniquel
D
D
Triebel
F
F
D015703:Antigens, CD; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002999:Clone Cells; D015536:Down-Regulation / Q000276:immunology*; D005822:Genetic Vectors / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000737:chemistry* / Q000276:immunology; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human; C000720328:soluble LAG-3 protein, human