Soluble human lymphocyte activation gene-3 modulates allospecific T cell responses.
Lymphocyte activation gene (LAG)-3, a member of the Ig superfamily, has been characterized as an activation antigen of T cells and NK cells. LAG-3 has been proposed as an alternate ligand for HLA class II due to some sequence homology and similarities in exon-intron organization with CD4. Here, we report the functional evaluation of a soluble Ig fusion molecule of human LAG-3 (LAG-3-Ig) in T cell activation assays. Cytofluorimetry studies revealed LAG-3-Ig binding predominantly to class II-expressing cells. In functional assays, inhibition of primary allogeneic mixed lymphocyte response (MLR) and murine-human xenogeneic MLR was observed in the presence of LAG-3-Ig. Effects of LAG-3-Ig addition were not observed on mitogen-, recall antigen- or superantigen-mediated stimulation. Cytotoxic T lymphocyte effector functions were also not affected by LAG-3-Ig. Inhibition of alloresponses by LAG-3-Ig occurred within the first 24 h of activation, resulting in a strong inhibition of IL-2 production. Unlike blockade of the CD28 receptor, however, LAG-3-Ig-mediated inhibition could not be reversed by exogenous IL-2 supplementation. Cytofluorimetric analysis of the phenotype of cells exposed to LAG-3-Ig in MLR cultures revealed a decrease in IL-2 receptor expression (CD25) on CD4+ cells in all donors tested. Based on the results from these studies, we conclude that LAG-3-Ig inhibits alloresponses of naive peripheral blood lymphocytes, by blocking the activation of a subpopulation of allo reactive cells.
Subramanyam
M
M
Department of Experimental Therapeutics, Ares Advanced Technology, Randolph, MA 02368, USA.
Wands
G
G
Nabioullin
R
R
Tepper
M A
MA
D000818:Animals; D015703:Antigens, CD; D015478:Antigens, Heterophile; D001427:Bacterial Toxins; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000097:blood; D007519:Isoantigens; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012995:Solubility; D018089:Superantigens / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D015478:Antigens, Heterophile; D001427:Bacterial Toxins; D017931:DNA Primers; D004768:Enterotoxins; D007376:Interleukin-2; D007519:Isoantigens; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D013745:Tetanus Toxoid; C030107:enterotoxin F, Staphylococcal; D000093322:Lymphocyte Activation Gene 3 Protein