Induction of antigen-specific regulatory T cells following overexpression of a Notch ligand by human B lymphocytes.
In mice, activation of the Notch pathway in T cells by antigen-presenting cells overexpressing Notch ligands favors differentiation of regulatory T lymphocytes responsible for antigen-specific tolerance. To determine whether this mechanism operates in human T cells, we used Epstein-Barr virus-positive lymphoblastoid cell lines (EBV-LCL) as our (viral) antigen-presenting cells and overexpressed the Notch ligand Jagged-1 (EBV-LCL J1) by adenoviral transduction. The EBV-LCL J1s were cocultured with autologous T cells, and the proliferative and cytotoxic responses to EBV antigens were measured. Transduction had no effect on EBV-LCL expression of major histocompatibility complex (MHC) antigens or of costimulatory molecules CD80, CD86, and CD40. However, we observed a 35% inhibition of proliferation and a >65% reduction in cytotoxic-T-cell activity, and interleukin 10 production was increased ninefold. These EBV-LCL J1-stimulated T lymphocytes act as antigen-specific regulatory cells, since their addition to fresh autologous T cells cultured with autologous nontransduced EBV-LCL cells significantly inhibited both proliferation and cytotoxic effector function. Within the inhibitory population, CD4(+)CD25(+) and CD8(+)CD25(-) T cells had the greatest activity. This inhibition appears to be antigen-specific, since responses to Candida and cytomegalovirus antigens were unaffected. Hence, transgenic expression of Jagged-1 by antigen-presenting cells can induce antigen-specific regulatory T cells in humans and modify immune responses to viral antigens.
D000328:Adult; D000956:Antigens, Viral / Q000276:immunology*; D001402:B-Lymphocytes / Q000502:physiology*; D002135:Calcium-Binding Proteins; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D016130:Immunophenotyping; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000502:physiology*; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D013601:T-Lymphocytes / Q000276:immunology*
D000956:Antigens, Viral; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins