Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice.
CD8+ islet cell-specific CTL lines and clones were established from lymphocytes infiltrating the pancreatic islets of acutely diabetic nonobese diabetic (NOD) mice from two subcolonies (NOD/Yn and NOD/Lt). CTL from NOD/Yn mice were predominantly cytotoxic against H-2b+ islet cells and to a lesser extent against H-2d+ islet cells. On the other hand, CTL from NOD/Lt mice were cytotoxic against H-2d+ but not against H-2b+ islet cells. Three of four CTL clones derived from NOD/Yn mice were H-2Db restricted, whereas two of two CTL clones derived from NOD/Lt mice were H-2Kd restricted. However, all of the H-2Kd restricted T cell clones expressed the same TCR, regardless of the NOD subcolony from which they were derived, compatible with a restricted repertoire. When two representative CTL clones were transferred into irradiated young NOD mice, neither induced insulitis or diabetes. However, transfer of these clones, together with CD4(+)-rich NOD splenocytes depleted of CD8+ T cells, caused severe insulitis and diabetes. When recipient NOD mice were treated with anti-CD4 mAbs, none of the mice developed insulitis or diabetes. Most of the irradiated NOD mice that received CD8-depleted splenocytes alone did not become diabetic. Through these studies we show that CTL clones can destroy pancreatic beta-cells as final effectors but that these clones require signals from CD4+ T cells to effect beta-cell damage.
Nagata
M
M
Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Alberta, Canada.
Santamaria
P
P
Kawamura
T
T
Utsugi
T
T
Yoon
J W
JW
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D016827:CD8 Antigens / Q000032:analysis*; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D006183:H-2 Antigens / Q000276:immunology; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*
D016827:CD8 Antigens; D006183:H-2 Antigens; C024755:H-2K(K) antigen