Human T-Cell Clonal Anergy is Induced by Antigen Presentation in the Absence of B7 Costimulation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 14; pp. 6586 - 6590
• Main Authors: Gimmi, Claude D., Freeman, Gordon J., Gribben, John G., Gray, Gary, Nadler, Lee M.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.07.1993; National Acad Sciences; National Academy of Sciences
• Subjects: 3T3 cells; Amino Acid Sequence; Antibody Formation - immunology; Antigen-Presenting Cells - immunology; Antigens; Antigens, Surface - immunology; Apoptosis - drug effects; B7-1 Antigen; Biological and medical sciences; Cell Survival; CHO cells; Clonal anergy; Clone Cells - immunology; Cultured cells; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes, MHC Class II - immunology; HLA-DR7 Antigen - immunology; Humans; Immune tolerance; Immunity (Disease); Immunobiology; Immunological tolerance; Interleukin-2 - deficiency; Lymphocyte Activation - immunology; Mice; Molecular Sequence Data; Molecules; Secretion; T lymphocytes; T-Lymphocytes - immunology; Tetanus Toxoid - immunology; Human; Antigen presentation; Immune response; Anergy; Ligand; Major histocompatibility system; Class II histocompatibility antigen; Accessory cell; Cellular immunity; Mechanism; Immune tolerance; T-Lymphocyte; Models; Clone
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.14.6586

The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex class II molecule as well as the delivery of one or more costimulatory signals provided by the antigen-presenting cell (APC). Although a number of candidate molecules have been identified that are capable of delivering a costimulatory signal, increasing evidence suggests that one such critical pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7, expressed on APCs. In view of the number of potential costimulatory molecules that might be expressed on the cell surface of APCs, artificial APCs were constructed by stable transfection of NIH 3T3 cells with HLA-DR7, B7, or both. Here, we show that in a human antigen-specific model system, when tetanus toxoid peptide antigen is presented by cells cotransfected with HLA-DR7 and B7, optimal T-cell proliferation and interleukin 2 production result. In contrast, antigen presentation, in the absence of B7 costimulation, results in T-cell clonal anergy. These results demonstrate that it is possible to induce antigen-specific clonal tolerance in human T cells that have been previously sensitized to antigen. The artificial antigen-presenting system provides a useful model for the investigation of the biochemical events involved in the generation of tolerance and for the study of signals necessary to overcome tolerance.