Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis

Abstract

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) β chain, TRBV31, with different Vα chains. Immunization of huB100tgxLdlr−/− mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.

Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis – A review of the experimental evidence

“…Intravenous administration of dendritic cells pulsed with the complete apoB protein and IL-10 reduces atherosclerosis by a mechanism involving activation of regulatory T cells (56). Taken together, these data imply that immunizations with self-antigens boosts existing regulatory T cell immunity and that breaking the tolerance to self-antigens may be an important contributor to atherosclerosis development (49,57). The first of these therapies are now close to entering clinical testing, emphasizing the need for a better understanding of the role of regulatory T cells in cardiovascular disease in humans.…”

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

“…Documented local self-antigens include heat shock proteins, oxidized LDL, and native lipoproteins (1)(2)(3)(4)(5)(6)(7)(8). Most recently, we have demonstrated autoimmunity to the ␣1(V) chain of col(V) to be a consistent feature of atherosclerosis in human CAD and in the Apoe Ϫ/Ϫ mouse model (17).…”

“…It is increasingly accepted that autoimmunity constitutes some portion of the pathological processes underlying atherosclerosis, with oxidized LDLs, native lipoproteins, and heat shock proteins identified as autoantigens involved in atherogenesis (1)(2)(3)(4)(5)(6)(7)(8). Recognition of the autoimmune aspects of atherosclerosis has suggested the possibility of employing immunomodulatory approaches to ameliorate symptoms.…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…Autoantibodies and autoreactive T cells against atherosclerotic plaque-derived antigens, such as HSPs, and LDL-or oxidized LDL-derived components (lysoPC, phosphorylcholine, ApoB100) have been identified, 21 and the disease could be induced by transfer of oxLDL-reactive T cells, 22 whereas blockade of ApoB100-reactive T cells has been shown to be protective. 23 Although atherosclerotic CVD is more prevalent than most of the classical autoimmune diseases, both have many similarities, Immunomodulation of Atherosclerosis (most often an NLRP [NOD-like receptor]), pro-caspase-1, and an adaptor protein, called apoptosis-associated speck-like protein containing CARD (ASC). Formed in response to exogenous or endogenous stimuli, such as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the inflammasome cleaves pro-IL-1β to generate mature and active IL-1β that is later secreted.…”

“…53 The inflammasome is a cytosolic multiprotein complex, typically comprising a sensor protein KETELHUTH DF et al 85 This approach has been tested for atherosclerosis, wherein immunization against a peptide from the T cell receptor β variable 31 (TRBV31), a TCR β chain that recognizes ApoB100, substantially mitigated experimental disease. 23 T cells, particularly naïve cells, depend highly on costimulation for their activation. Thus, targeting surface costimulatory molecules has been considered in an attempt to control T cell-mediated responses.…”