Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice
Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice
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DOI：
10.4049/jimmunol.168.12.6159
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发表时间：
2002-06-15
影响因子：
4.4
通讯作者：
Vaupel, BA
中科院分区：
文献类型：
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作者：
Kanagawa, O;Militech, A;Vaupel, BA
携带来自胰岛Ag特异性CD4 T细胞克隆BDC2.5的转基因TCR的非肥胖糖尿病（NOD）小鼠不会发生糖尿病。相比之下，相同的SCID背景转基因NOD小鼠在出生后4周内就会患上糖尿病。利用新开发的针对BDC2.5 TCR的单克隆抗体，我们检测了NOD. BDC转基因小鼠中致糖尿病T细胞和调节性T细胞之间的相互作用。来自NOD.BDC小鼠的CD4 T细胞表达高水平的克隆型，将糖尿病转移给NOD.SCID受体。相比之下，由于转基因和内源性TCR α链的表达而表达低水平的CD4 T细胞抑制糖尿病转移。克隆型低的CD4 T细胞出现在胸腺和外周淋巴器官的个体发育后期，与环磷酰胺诱导的糖尿病的抗性一致。这些结果表明NOD. BDC小鼠的糖尿病过程受致糖尿病性T细胞和调节性T细胞之间的平衡调节。在缺乏特异性操作的情况下，调节性T细胞功能似乎占主导地位，小鼠保持无糖尿病。了解调节性T细胞抑制糖尿病发生过程的机制将为预防高危人群中糖尿病的发生提供手段。
Nonobese diabetic (NOD) mice carrying a transgenic TCR from an islet Ag-specific CD4 T cell clone, BDC2.5, do not develop diabetes. In contrast, the same transgenic NOD mice on the SCID background develop diabetes within 4 wk after birth. Using a newly developed mAb specific for the BDC2.5 TCR, we examined the interaction between diabetogenic T cells and regulatory T cells in NOD.BDC transgenic mice. CD4 T cells from NOD.BDC mice, expressing high levels of the clonotype, transfer diabetes to NOD.SCID recipients. In contrast, CD4 T cells expressing low levels due to the expression of both transgenic and endogenous TCR a-chains inhibit diabetes transfer. The clonotype-low CD4 T cells appear late in the ontogeny in the thymus and peripheral lymphoid organs, coinciding with resistance to cyclophosphamide-induced diabetes. These results demonstrate that diabetic processes in NOD.BDC mice are regulated by a balance between diabetogenic T cells and regulatory T cells. In the absence of specific manipulation, regulatory T cell function seems to be dominant and mice remain diabetes free. Understanding of mechanisms by which regulatory T cells inhibit diabetogenic processes would provide means to prevent diabetes development in high-risk human populations.