Cross-linking of CD80 on CD4+ T cells activates a calcium-dependent signaling pathway.
CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4+ T cells via CD28 during activation. However, CD80 is also expressed on the surface of activated CD4+ T cells, and cross-linking CD80 on the surface of CD4+ T cells activated in the presence of Th1-promoting cytokines induces a direct up-regulation of T-bet, IFN-gamma, and Bcl(XL) expression in primary CD4+ T cells. The present data show that naive CD4+ T cells activated in Th1-promoting conditions in the presence of anti-CD80 mAb increase the level of IFN-gamma produced by increasing the rate of IFN-gamma mRNA transcription, which is supported by an increase in the level of T-bet phosphorylation and T-bet binding to the third intronic enhancer in the IFN-gamma locus. Furthermore, anti-CD80 mAb-induced increase in IFN-gamma expression and T-bet phosphorylation is dependent upon the activation of a Ca2+-dependent pathway as shown by anti-CD80 mAb-induced intracellular Ca2+ flux following CD80 cross-linking. These findings indicate a novel regulatory role for CD80-mediated intracellular signals in CD4+ T cells and have important implications for disease therapies using anti-costimulatory mAbs as use of an intact CD80 mAb may lead to CD80 cross-linking on activated T cells and enhanced proinflammatory cytokine production.
Podojil
Joseph R
JR
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Miller
Stephen D
SD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D001666:Binding Sites, Antibody; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D000098815:T-bet Transcription Factor
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D003432:Cross-Linking Reagents; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma