Combined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice

This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-Ldlr(-/-) Rag1(-/-) mice, which show severe combined B- and T-cell immunodeficiency and C-Ldlr(-/-) Rag1(-/-) Il2rg(-/-) mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western type diet (WTD). Both B6-Ldlr(-/-) and C-Ldlr(-/-) immunocompetent mice were used as controls. Body weights and serum cholesterol levels of both immunodeficient strains were significantly increased compared to C-Ldlr(-/-) controls, except for cholesterol levels of C-Ldlr(-/-) Rag1(-/-) double mutants after 12 weeks on the WTD. Quantification of the aortic sinus plaque area revealed that both strains of immunodeficient mice developed significantly more atherosclerosis compared to C-Ldlr(-/-) controls after 24 weeks on the WTD. Increased atherosclerotic lesion development in C-Ldlr(-/-) Rag1(-/-) Il2rg(-/-) triple mutants was associated with significantly increased numbers of macrophages and significantly decreased numbers of smooth muscle cells compared to both C-Ldlr(-/-) wild type and C-Ldlr(-/-) Rag1(-/-) double mutants pointing to a plaque destabilizing effect of NK cell loss. Collectively, the present study reveals a previously unappreciated complexity with regard to the impact of lymphocytes on lipoprotein metabolism and the role of lymphocyte subsets in plaque composition.