Matsumoto M, Yagi H, Kunimoto K, Kawaguchi J, Makino S, Harada M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Cell Immunol. 1993 Apr 15;148(1):189-97. doi: 10.1006/cimm.1993.1101.
The NOD mouse, which spontaneously develops insulitis and overt diabetes, is a model of autoimmune type I diabetes mellitus. To analyze of the roles of CD4+ and CD8+ T cells in the pathogenesis of this mouse, we have been doing a series of studies on the induction of insulitis and diabetes in NOD athymic nude mice by means of T cell transfer. To complement our previous study dealing with the induction of insulitis and cyclophosphamide-induced diabetes in recipients that had been reconstituted with each T cell subset derived from the nondiabetic mice, the present study was conducted to observe the transfer of spontaneous diabetes by injecting T cells harvested from diabetic mice. Any possible in vivo increase in the contaminating T cell subset was prevented by injecting the antibody homologous to it. Transfer of untreated or complement-treated splenic lymphocytes of diabetic mice containing both T cell subsets induced spontaneous diabetes 30 to 58 days after the cell transfer as well as insulitis, while spleen cells from nondiabetic mice rarely produced diabetes. On the other hand, transfer of either CD4+ cell-depleted or CD8+ cell-depleted splenic lymphocytes of diabetic mice did not cause diabetes at least up to 60 days after the cell transfer. Also, transfer of only the CD4+ T cell-depleted fraction did not cause insulitis. In contrast, transfer of only the CD8+ T cell-depleted fraction induced insulitis in all the recipients. However, insulitis was less potent in this group of mice than in the diabetic recipients given both subsets: only a low insulitis score was obtained and a number of beta-cells remained alive despite the insulitis in mice given the CD8+ T cell-depleted fraction, whereas islet damage was very severe and insulin-secreting beta-cells were no longer detected in the diabetic mice. Thus, the present results agree with the previous ones concerning transfer of diabetes, with the aid of cyclophosphamide treatment, by T cells of nondiabetic mouse origin. Consideration of our results together with earlier findings led to the conclusion that CD4+ T cells are primarily responsible for insulitis and that CD8+ T cells migrate into islets and are differentiated into mature killer cells against beta-cells with the aid of CD4+ T cells in both spontaneous and cyclophosphamide-induced diabetes.
非肥胖糖尿病（NOD）小鼠会自发发展为胰岛炎和明显的糖尿病，是自身免疫性I型糖尿病的一种模型。为了分析CD4⁺和CD8⁺ T细胞在该小鼠发病机制中的作用，我们一直在通过T细胞转移对NOD无胸腺裸鼠诱导胰岛炎和糖尿病进行一系列研究。为了补充我们之前关于用源自非糖尿病小鼠的每个T细胞亚群重建受体后诱导胰岛炎和环磷酰胺诱导糖尿病的研究，本研究通过注射从糖尿病小鼠收获的T细胞来观察自发性糖尿病的转移。通过注射与之同源的抗体来防止体内任何可能的污染T细胞亚群增加。含有两个T细胞亚群的糖尿病小鼠未经处理或经补体处理的脾淋巴细胞转移后，在细胞转移后30至58天诱导了自发性糖尿病以及胰岛炎，而非糖尿病小鼠的脾细胞很少引发糖尿病。另一方面，糖尿病小鼠的CD4⁺细胞耗竭或CD8⁺细胞耗竭的脾淋巴细胞转移至少在细胞转移后60天内未引发糖尿病。此外，仅CD4⁺ T细胞耗竭部分的转移未引发胰岛炎。相反，仅CD8⁺ T细胞耗竭部分的转移在所有受体中诱导了胰岛炎。然而，该组小鼠的胰岛炎比给予两个亚群的糖尿病受体中的胰岛炎要弱：尽管给予CD8⁺ T细胞耗竭部分的小鼠存在胰岛炎，但仅获得了较低的胰岛炎评分，并且仍有许多β细胞存活，而糖尿病小鼠的胰岛损伤非常严重，不再检测到胰岛素分泌β细胞。因此，本研究结果与之前关于用环磷酰胺处理辅助非糖尿病小鼠来源的T细胞转移糖尿病的结果一致。综合考虑我们的结果和早期发现得出结论，在自发性和环磷酰胺诱导的糖尿病中，CD4⁺ T细胞主要负责胰岛炎，并且CD8⁺ T细胞迁移到胰岛并在CD4⁺ T细胞的辅助下分化为针对β细胞的成熟杀伤细胞。
