Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice

Abstract

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-MDALDL 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. © 2010 American Heart Association, Inc.