Deficiency of Antigen-Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice

J Sun, K Hartvigsen, M. Y Chou, Y Zhang, G. K Sukhova, J Zhang, M Lopez Ilasaca, C. J Diehl, N Yakov, D Harats, J George, J. L Witztum, P Libby, H Ploegh and G. P. Shi

Circulation, 2010, 122(8), 808-820. DOI: 10.1161/CIRCULATIONAHA.109.891887


Background— Adaptive immunity and innate immunity play important roles in atherogenesis. Invariant chain (CD74) mediates antigen-presenting cell antigen presentation and T-cell activation. This study tested the hypothesis that CD74-deficient mice have reduced numbers of active T cells and resist atherogenesis.

Methods and Results— In low-density lipoprotein receptor–deficient (Ldlr–/–) mice, CD74 deficiency (Ldlr–/–Cd74–/–) significantly reduced atherosclerosis and CD25+-activated T cells in the atheromata. Although Ldlr–/–Cd74–/– mice had decreased levels of plasma immunoglobulin (Ig) G1, IgG2b, and IgG2c against malondialdehyde-modified LDL (MDA-LDL), presumably as a result of impaired antigen-presenting cell function, Ldlr–/–Cd74–/– mice showed higher levels of anti–MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr–/–Cd74–/– mice had lower levels of all anti–MDA-LDL Ig isotypes compared with Ldlr–/– mice. As anticipated, only Ldlr–/– splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 immunization enhanced atherogenesis in Ldlr–/– mice, but Ldlr–/– Cd74–/– mice remained protected. Compared with Ldlr–/– mice, Ldlr–/–Cd74–/– mice had higher anti–MDA-LDL autoantibody titers, fewer lesion CD25+-activated T cells, impaired release of Th1/Th2 cytokines from antigen-presenting cells after heat shock protein-65 stimulation, and reduced levels of all plasma anti–heat shock protein-65 Ig isotypes. Cytofluorimetry of splenocytes and peritoneal cavity cells of MDA-LDL– or heat shock protein-65–immunized mice showed increased percentages of autoantibody-producing marginal zone B and B-1 cells in Ldlr–/–Cd74–/– mice compared with Ldlr–/– mice.

Conclusions— Invariant chain deficiency in Ldlr–/– mice reduced atherosclerosis. This finding was associated with an impaired adaptive immune response to disease-specific antigens. Concomitantly, an unexpected increase in the number of innate-like peripheral B-1 cell populations occurred, resulting in increased IgM/IgG3 titers to the oxidation-specific epitopes.

ASCI-ID: 1433-371