Immunopathogenic role of TH1 cells in autoimmune diabetes: evidence from a T1 and T2 doubly transgenic non-obese diabetic mouse model.
To improve the feasibility of in vivo monitoring of autoreactive T cells in the diabetogenic process, we generated T1 and T2 doubly transgenic non-obese diabetic (NOD) mice in which transgenic human CD90 (hCD90) is simultaneously expressed on IFN-gamma-producing cells or murine CD90.1 (mCD90.1) is expressed on IL-4-producing cells. These transgenic NOD mice develop diabetes with the same kinetics and incidence as wild type NOD mice, permitting the physiological characterization of CD4(+)hCD90(+) cells, which represent T(H)1 cells in lymphoid organs and at the site of insulitis. CD4(+)hCD90(+) cells had a higher capacity to secret IFN-gamma than CD4(+)hCD90(-) cells in an autoantigen-specific manner. Transgenic mice treated with GAD65 plasmid were protected from autoimmune diabetes, and had a lower number of CD4(+)hCD90(+) cells, confirming the pathogenic role of CD4(+)hCD90(+) cells in autoimmune diabetes. To further investigate the effect of IL-12 on the development of T(H)1 cells in autoimmune diabetes, we crossed these doubly transgenic mice to IL-12p35-deficient NOD mice. Despite severe disturbance of diabetes in p35(-/-) mice, the frequency of T(H)1 cells in these mice was slightly lower than in wild type mice. These data support the pathological role of IL-12 in autoimmune diabetes and suggest the existence an IL-12-independent pathway of T(H)1 development.
Hung
Jung-Tung
JT
Graduate Institute of Life Sciences, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan.
Liao
Jen-Hsiang
JH
Lin
Yu-Chung
YC
Chang
Hsiu-Ying
HY
Wu
Shu-Fen
SF
Chang
Tsung-Hsien
TH
Kung
John T
JT
Hsieh
Shie-Liang
SL
McDevitt
Hugh
H
Sytwu
Huey-Kang
HK
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010957:Plasmids; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D018800:Thy-1 Antigens / Q000235:genetics*
D018800:Thy-1 Antigens; D018664:Interleukin-12