IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes.
We have generated transgenic nonobese diabetic (NOD) mice expressing dominant negative mutant IFN-gamma receptors on pancreatic beta cells to investigate whether the direct effects of IFN-gamma on beta cells contribute to autoimmune diabetes. We have also quantitated by flow cytometry the rise in class I MHC on beta cells of NOD mice with increasing age and degree of islet inflammatory infiltrate. Class I MHC expression increases gradually with age in wild-type NOD mice; however, no such increase is observed in the transgenic beta cells. The transgenic mice develop diabetes at a similar rate to that of wild-type animals. This study dissociates class I MHC upregulation from progression to diabetes, shows that the rise in class I MHC is due to local IFN-gamma action, and eliminates beta cells as the targets of IFN-gamma in autoimmune diabetes.
Thomas
H E
HE
Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
Parker
J L
JL
Schreiber
R D
RD
Kay
T W
TW
D019264:Adoptive Transfer; D000367:Age Factors; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D005260:Female; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D015994:Incidence; D007371:Interferon-gamma / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000235:genetics; D012737:Sex Factors; D013154:Spleen / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D003520:Cyclophosphamide; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor