HUMAN T-CELL CLONAL ANERGY IS INDUCED BY ANTIGEN PRESENTATION IN THE ABSENCE OF B7 COSTIMULATION
HUMAN T-CELL CLONAL ANERGY IS INDUCED BY ANTIGEN PRESENTATION IN THE ABSENCE OF B7 COSTIMULATION
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DOI：
10.1073/pnas.90.14.6586
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发表时间：
1993-07-15
影响因子：
11.1
通讯作者：
NADLER, LM
中科院分区：
文献类型：
--
作者：
GIMMI, CD;FREEMAN, GJ;NADLER, LM
T细胞对其抗原的最大反应需要由主要的组织相容性复合体II类分子递呈抗原，并由抗原提呈细胞(APC)提供一个或多个共刺激信号。尽管已经确定了一些能够传递共刺激信号的候选分子，但越来越多的证据表明，其中一个关键途径涉及T细胞表面抗原CD28与其配体B7的相互作用，该配体表达在APC上。鉴于APC细胞表面可能表达的潜在共刺激分子的数量，通过稳定地将人类白细胞抗原DR7、B7或两者共同转染NIH3T3细胞，构建了人工APC。在这里，我们证明了在人类抗原特异性的模型系统中，当破伤风类毒素抗原被共转染有人类白细胞抗原-DR7和B7的细胞呈递时，最佳的T细胞增殖和白介素2的产生结果。相反，在没有B7共刺激的情况下，抗原提呈会导致T细胞克隆性无能。这些结果表明，在先前对抗原致敏的人T细胞中诱导抗原特异性克隆耐受是可能的。人工抗原提呈系统为研究与耐受性产生有关的生化事件和研究克服耐受性所需的信号提供了有用的模型。
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.