COSTIMULATOR B7-1 CONFERS ANTIGEN-PRESENTING-CELL FUNCTION TO PARENCHYMAL TISSUE AND IN CONJUNCTION WITH TUMOR-NECROSIS-FACTOR-ALPHA LEADS TO AUTOIMMUNITY IN TRANSGENIC MICE
COSTIMULATOR B7-1 CONFERS ANTIGEN-PRESENTING-CELL FUNCTION TO PARENCHYMAL TISSUE AND IN CONJUNCTION WITH TUMOR-NECROSIS-FACTOR-ALPHA LEADS TO AUTOIMMUNITY IN TRANSGENIC MICE
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DOI：
10.1073/pnas.91.11.5138
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发表时间：
1994-05-24
影响因子：
11.1
通讯作者：
FLAVELL, RA
中科院分区：
文献类型：
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作者：
GUERDER, S;PICARELLA, DE;FLAVELL, RA
对外周抗原的耐受性被认为是由实质组织不能刺激T细胞引起的，这种不能被认为与缺乏T细胞活化所需的共刺激信号的表达有关。为了测试该模型，我们产生了在胰腺β细胞上表达共刺激分子B7-1的转基因小鼠。我们发现这些转基因小鼠的胰岛在体外和体内对幼稚T细胞具有免疫原性。尽管如此，在β细胞上特异性表达共刺激分子B7-1的小鼠不发展糖尿病，表明B7-1共刺激分子的表达不足以消除对外周抗原的耐受性。我们已经报道了β细胞表达的肿瘤坏死因子α亚单位（TNF-α）导致局部炎症，但不破坏胰岛。然而，引人注目的是，由于细胞因子TNF-α的表达和B7-1的表达引起的局部炎症的组合导致组织破坏和糖尿病。
Tolerance to peripheral antigens is thought to result from the inability of parenchymal tissue to stimulate T cells-an inability that is believed to relate to the lack of expression of the costimulatory signal(s) required for T-cell activation. To test this model, we generated transgenic mice expressing costimulatory molecule B7-1 on the beta cells of the pancreas. We find that islets from these transgenic mice are immunogenic for naive T cells in vitro and in vivo. Nonetheless, mice expressing the costimulator B7-1 specifically on beta cells do not develop diabetes, suggesting that expression of the B7-1 costimulator is not sufficient to abrogate the tolerance to peripheral antigens. We have reported that tumor necrosis factor alpha subunit (TNF-alpha) expressed by beta cells leads to a local inflammation but no islet destruction. Strikingly, however, the combination of a local inflammation due to the expression of the cytokine TNF-alpha and the expression of B7-1 results in tissue destruction and diabetes.