Yagi H, Matsumoto M, Kunimoto K, Kawaguchi J, Makino S, Harada M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Eur J Immunol. 1992 Sep;22(9):2387-93. doi: 10.1002/eji.1830220931.
The NOD mouse, which spontaneously develops insulitis and overt diabetes, is a model of autoimmune type I diabetes mellitus. For the precise analysis of the roles of CD4+ and CD8+ T cells in the pathogenesis of this mouse, these subsets must be transferred into recipients that are completely free of T cells and pathological changes. We used athymic NOD nude mice, which congenitally lack mature T cells and are free of insulitis and hyperglycemia up to the age of 60 weeks, as recipients for this purpose. To the nude recipients we transferred either one of a highly purified CD4+ or CD8+ T cell subset derived from non-diabetic female NOD mice; any in vivo increase in the contaminating T cell subsets was prevented by injecting the antibody homologous to it. Most of the T cell-reconstituted recipients were treated with cyclophosphamide to promote the onset of overt diabetes. Transfer of the CD8+ T cell subset alone did not induce insulitis or hyperglycemia. In contrast, transfer of the CD4+ T cell subset alone produced insulitis, but not hyperglycemia, in all the recipients. However, the subsequent transfer of CD8+ T cells into CD4+ T cell-reconstituted recipients induced severe insulitis and hyperglycemia in almost all the recipients. In these diabetic recipients, we observed severe damage of the pancreatic islets and the infiltration of a large number of CD8+ T cells into the remaining islets; insulin-secreting beta cells were no longer detected. These results suggest that CD4+ T cells play a predominant role in the development of insulitis and that CD8+ T cells migrate into the islets and are subsequently, with the aid of CD4+ T cells, differentiated into killer cells which act against beta cells.
非肥胖型糖尿病（NOD）小鼠会自发发生胰岛炎并发展为明显的糖尿病，是自身免疫性I型糖尿病的一种模型。为了精确分析CD4⁺和CD8⁺T细胞在该小鼠发病机制中的作用，必须将这些亚群转移到完全没有T细胞和病理变化的受体中。为此，我们使用了无胸腺NOD裸鼠，它们先天性缺乏成熟T细胞，在60周龄之前没有胰岛炎和高血糖症，作为受体。我们将来自非糖尿病雌性NOD小鼠的高度纯化的CD4⁺或CD8⁺T细胞亚群之一转移到裸鼠受体中；通过注射与之同源的抗体来防止污染的T细胞亚群在体内增加。大多数T细胞重建的受体用环磷酰胺处理以促进明显糖尿病的发生。单独转移CD8⁺T细胞亚群不会诱导胰岛炎或高血糖症。相反，单独转移CD4⁺T细胞亚群在所有受体中都会产生胰岛炎，但不会产生高血糖症。然而，随后将CD8⁺T细胞转移到CD4⁺T细胞重建的受体中，几乎在所有受体中都诱导了严重的胰岛炎和高血糖症。在这些糖尿病受体中，我们观察到胰岛严重受损，大量CD8⁺T细胞浸润到剩余的胰岛中；不再检测到分泌胰岛素的β细胞。这些结果表明，CD4⁺T细胞在胰岛炎的发展中起主要作用，并且CD8⁺T细胞迁移到胰岛中，随后在CD4⁺T细胞的帮助下分化为针对β细胞的杀伤细胞。
