Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice.
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.
Yagi
H
H
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Matsumoto
M
M
Kunimoto
K
K
Kawaguchi
J
J
Makino
S
S
Harada
M
M
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis*; D016827:CD8 Antigens / Q000032:analysis*; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D003520:Cyclophosphamide