Murine lupus in MRL/lpr mice lacking CD4 or CD8 T cells.
MRL/lpr mice develop a systemic autoimmune disease similar to systemic lupus erythematosus in humans. The mice show progressive lymphadenopathy due to the accumulation of an unusual population of CD4-8-(DN) B220+ alpha beta+ T cells. We bred MRL/lpr mice with mice lacking CD4+ or CD8+ T cells by gene targeting via homologous recombination in embryonal stem cells to determine the roles of these cells in the autoimmune disease. No difference in survival or autoantibody levels was noted between CD8-/-lpr and littermate controls. Interestingly, these CD8-/- lpr mice have a reduced level of B220+ DN T cells despite the fact that the degree of lymphadenopathy was unaltered. CD4-/- lpr mice had a diminished autoimmune disease with a reduction in autoantibody production and skin vasculitits, and increased survival compared to littermate controls. However, CD4-/- lpr mice had an enhanced splenomegaly that developed massively by 16-20 weeks of age (5 to 8 greater than lpr control mice) due to the accumulation of DN B220+ T cells. In addition, there were no differences in peripheral lymph node enlargement, although the proportion of DN B220+ T cells was about twofold higher in the CD4-/- lpr mice. These cells were phenotypically identical to the DN population in control lpr mice, indicating that the accumulating DN T cells can be dissociated from the autoimmune disease in these mice. Collectively, our results reveal that the autoimmune disease is dependent on CD4+, but not CD8+ T cells, and that many of the B220+ DN T cells traverse a CD8 developmental pathway.
Koh
D R
DR
Amgen Research Institute, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Canada.
Ho
A
A
Rahemtulla
A
A
Fung-Leung
W P
WP
Griesser
H
H
Mak
T W
TW
D000818:Animals; D001483:Base Sequence; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000276:immunology*; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000276:immunology; D008099:Liver / Q000196:embryology / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D011817:Rabbits
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region