Enhanced lymphoproliferation and diminished autoimmunity in CD4-deficient MRL/lpr mice.
MRL/lpr mice spontaneously develop an autoimmune disease with features of systemic lupus erythematosus. They also develop a lymphoproliferative disorder characterized by a massive accumulation of double-negative (DN) T cells that lack both CD4 and CD8. To clarify the role of CD4 in autoimmunity and lymphoproliferation in these mice, CD4-deficient MRL/lpr mice were generated. CD4-deficient MRL/lpr mice developed massive expansion of DN T cells in the blood, spleen, and lymph nodes, which significantly exceeded the degree of lymphoproliferation in CD4-expressing control MRL/lpr mice. Despite this lymphoproliferation, CD4-deficient MRL/lpr mice produced little, if any, antibodies to double-stranded DNA, and they had prolonged survival relative to CD4-expressing littermates. However, they eventually developed moderately severe nephritis, characterized by immunoglobulin and complement deposition in glomeruli, vasculitis, and renal infiltration by CD8+ T cells. These findings indicate that (1) lymphoproliferation in MRL/lpr mice does not require the expression of CD4; (2) autoantibody production in MRL/lpr mice is dependent on the expression of CD4 and not on the accumulation of DN T cells; and (3) the development of nephritis in MRL/lpr mice involves both CD4-dependent and CD4-independent mechanisms.
Chesnutt
M S
MS
Department of Medicine, Department of Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Finck
B K
BK
Killeen
N
N
Connolly
M K
MK
Goodman
H
H
Wofsy
D
D
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007674:Kidney Diseases / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000276:immunology*; D018345:Mice, Knockout; D012330:RNA, Double-Stranded / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000974:Antibodies, Antinuclear; D015704:CD4 Antigens; D012330:RNA, Double-Stranded