Autoreactive diabetogenic T-cells in NOD mice can efficiently expand from a greatly reduced precursor pool
Autoreactive diabetogenic T-cells in NOD mice can efficiently expand from a greatly reduced precursor pool
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DOI：
10.2337/diabetes.50.9.1992
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发表时间：
2001-09-01
期刊：
影响因子：
7.7
通讯作者：
Joyce, S
中科院分区：
文献类型：
--
作者：
Serreze, DV;Johnson, EA;Joyce, S
广泛的胰腺β细胞自身反应性t细胞通常有助于NOD小鼠I型糖尿病的发展。然而，自身反应性t细胞的前体池的大量减少是否会抑制1型糖尿病的发展尚不清楚。为了解决这一问题，我们通过转基因表达H2-D-b类限制性t细胞受体（TCR）来减少NOD小鼠自身反应性t细胞的前体频率，该受体是病理学无关的淋巴细胞脉络丛脑膜炎病毒（LCMV）肽的特异性。TCR等位基因的排除大大减少了这些NOD中可产生致糖尿病效应物的t细胞池。LCMV TCR Tg小鼠。令人惊讶的是，这并没有降低他们对1型糖尿病的易感性。此外，在标准NOD小鼠中普遍存在的致糖尿病性CD8 t细胞群在NOD的胰岛中基本相同。LCMV TCR Tg小鼠。其他数据表明，这些CD8 t细胞的抗原特异性主要是共享TCR-a链的功能。虽然与B6、D2对照小鼠相比，NOD株中TCR转基因t细胞的百分比有所下降，但NOD株中积累的TCR转基因和非转基因t细胞的总数都要高得多。这种缺乏同源肽的转基因t细胞积累表明NOD遗传背景优先促进高效抗原非依赖性t细胞扩增。这可能允许NOD小鼠中的糖尿病源性t细胞在遇到抗原之前进行有效扩增，这可能是发病机制中一个重要的、以前未被考虑的方面。
A broad repertoire of pancreatic beta -cell autoreactive T-cells normally contributes to the development of type I diabetes in NOD mice. However, it has been unknown if a large reduction in the precursor pool from which autoreactive T-cells are drawn would inhibit the development of type 1 diabetes. To address this issue, we reduced the precursor frequency of autoreactive T-cells in NOD mice through allelic exclusion induced by transgenic expression of an H2-D-b class I-restricted T-cell receptor (TCR) specific for a pathologically irrelevant lymphocytic choriomeningitis virus (LCMV) peptide. TCR allelic exclusion greatly reduced the pool of T-cells from which diabetogenic effectors could be derived in these NOD.LCMV TCR Tg mice. Surprisingly, this did not impair their type I diabetes susceptibility. Furthermore, a diabetogenic CD8 T-cell population that is prevalent in standard NOD mice was present at essentially equivalent levels in pancreatic islets of NOD.LCMV TCR Tg mice. Other data indicated that the antigenic specificity of these CD8 T-cells is primarily the function of a shared TCR-a chain. Although the percentage of TCR transgenic T-cells decreased in NOD versus B6,D2 control mice, much higher total numbers of both the TCR transgenic and the nontransgenic T-cells accumulated in the NOD strain. This transgenic T-cell accumulation in the absence of the cognate peptide indicated that the NOD genetic background preferentially promotes a highly efficient antigen-independent T-cell expansion. This might allow diabetogenic T-cells in NOD mice to undergo an efficient expansion before encountering antigen, which would represent an important and previously unconsidered aspect of pathogenesis.