CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling.
The lymphocyte activation gene-3 (LAG-3) molecule is a T cell activation Ag closely related to CD4 at the gene and protein levels. We investigated whether LAG-3 itself may down-regulate the immune response by interfering with TCR signaling. The binding of Ab to the LAG-3 molecule followed by cross-linking (XL) inhibits cell proliferation and cytokine secretion in response to CD3XL on activated T cells. LAG-3XL-induced down-regulation is associated with functional unresponsiveness, as well as with high CD25 expression levels and reversion by exogenous IL-2. It is also associated with a down-modulation of CD3/TCR complex expression. At the biochemical level, LAG-3XL inhibits calcium response to CD3 stimulation. This inhibition is observed with different LAG-3- and CD3-specific mAbs on condition that the two receptors are cross-linked together. Finally, the capping of CD3 was shown to induce cocapping of LAG-3 molecules. Together, these results show that CD3/TCR complex-associated LAG-3 molecules can play an active role in negatively regulating the CD3/TCR activation pathway. They ultimately suggest that LAG-3 is an inhibitory receptor in activated T lymphocytes.
Laboratoire d'Immunologie Cellulaire, Institut Gustave-Roussy, Villejuif, France.
S
S
Hannier
M
M
Tournier
G
G
Bismuth
F
F
Triebel
D015703:Antigens, CD; D017252:CD3 Complex / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D017252:CD3 Complex; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human