T-cell receptor transgenic response to an endogenous polymorphic autoantigen determines susceptibility to diabetes
T-cell receptor transgenic response to an endogenous polymorphic autoantigen determines susceptibility to diabetes
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DOI：
10.2337/diabetes.53.4.978
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发表时间：
2004-04-01
期刊：
影响因子：
7.7
通讯作者：
Haskins, K
中科院分区：
文献类型：
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作者：
Pauza, ME;Dobbs, CM;Haskins, K
我们建立了一只T细胞受体（TCR）转基因NOD小鼠，6.9TCR/NOD，其中致糖尿病性T细胞和天然存在的自身抗原的表达同时受到控制。亲本T细胞克隆BDC-6.9和来自6.9TCR/NOD小鼠的T细胞识别NOD中存在的目前未鉴定的抗原，但不识别BALB/c胰岛细胞中的抗原。编码抗原的基因或调节抗原的蛋白质先前已被映射到6号染色体上的一个基因座。我们在NOD同源背景下开发了携带来自BDC-6.9 T细胞克隆的TCR α和β链的转基因小鼠，其中NOD小鼠6号染色体上的抗原基因座被来自BALB/c的片段取代。这些NOD.C6同源小鼠缺乏BDC-6.9 T细胞克隆应答的NOD胰岛细胞抗原。在雄性和雌性6.9TCR/NOD小鼠中糖尿病显著加速，但在缺乏NOD胰岛细胞自身抗原的6.9TCR/NOD.C6小鼠中，我们没有观察到长达1岁的糖尿病。因此，6.9TCR转基因小鼠的产生提供了自身免疫性糖尿病的模型，由此内源性多态性自身抗原的受控表达有效地决定了疾病的发展。
We have produced a T-cell receptor (TCR) transgenic NOD mouse, 6.9TCR/NOD, in which the expression of both diabetogenic T-cells and naturally occurring antoantigen were simultaneously controlled. The parent T-cell clone, BDC-6.9, and T-cells from 6.9TCR/NOD mice recognize a currently unidentified antigen present in NOD but not in BALB/c islet cells. A gene that codes for the antigen, or a protein that regulates the antigen, was previously mapped to a locus on chromosome 6. We have developed transgenic mice bearing the TCR alpha- and beta-chains from the BDC-6.9 T-cell clone on a NOD congenic background in which the antigen locus on chromosome 6 of the NOD mouse is replaced by a segment from BALB/c. These NOD.C6 congenic mice lack the NOD islet cell antigen to which the BDC-6.9 T-cell clone responds. Diabetes in both male and female 6.9TCR/NOD mice is dramatically accelerated, but in 6.9TCR/NOD.C6 mice lacking the NOD islet cell autoantigen, we have not observed diabetes for up to I year of age. Thus, the generation of 6.9TCR transgenic mice provides a model of autoimmune diabetes whereby controlled expression of an endogenous polymorphic autoantigen effectively determines disease development.