Induction of Dendritic Cell–Mediated T-Cell Activation by Modified but Not Native Low-Density Lipoprotein in Humans and Inhibition by Annexin A5

Abstract

Objective— Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation (oxLDL) or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis. We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein E −/− mice. Here, we focus on the LDLx effects on human DCs and T cells. Approach and Results— Human DCs were differentiated from peripheral blood monocytes, stimulated by oxLDL or LDLx. Naive autologous T cells were cocultured with pretreated DCs. oxLDL and LDLx, in contrast to LDL, induced DC-activation and T-cell proliferation. T cells exposed to LDLx-treated DCs produced interferon-γ, interleukin (IL)-17 but not IL-4 and IL-10. Annexin A5 abrogated LDLx effects on DCs and T cells and increased production of transforming growth factor-β and IL-10. Furthermore, IL-10 producing T cells suppressed primary T-cell activation via soluble IL-10, transforming growth factor-β, and cell–cell contact. Lentiviral-mediated shRNA knock-down HSP60 and 90 in DCs attenuated the effect of LDLx on DCs and subsequent T-cell proliferation. Experiments on DC and T cells derived from carotid atherosclerotic plaques gave similar results. Conclusions— Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 and 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent.

A novel anti-inflammatory mechanism of high density lipoprotein through up-regulating annexin A1 in vascular endothelial cells

“…In the present study, we first demonstrated that TNF-α decreased endothelial ANXA1 in vitro and in vivo, which may help researchers clarify why ANXA1 exists in control EMPs while not in TNF-α EMPs. In addition, accumulated studies reported that Annexin A5 (ANXA5), another member of annexin superfamily, exerted athero-protective roles through inhibiting pro-inflammatory effects, vascular protective effects and induction of T-cell activation, which played key roles in the development of CVD [27][28][29]. This work indicated that HDL significantly reversed the trend of TNF-α d6ecreasing ANXA1 in endothelial cells, inhibiting monocyte-endothelial cells adhesion.…”

C reactive protein and enzymatically modified LDL cooperatively promote dendritic cell-mediated T cell activation

“…Different types of LDL behaved and functioned differently [26,31]. Oxidized LDL induced expression of scavenger receptors and lipid storage in the acidic compartment, increased cellular content of the endolysosomal signature lipid bis(monoacylglycero)phosphate, and activated proapoptotic signaling, whereas eLDL caused expansion of cholesterol-and sphingomyelin-enriched surface membrane microdomains, up-regulation of receptors required for phagocytosis of eLDL, formation of lipid droplet, and increased endoplasmic reticulum stress [31].…”

“…Blockade of transforming growth factor-β signaling in T cells reduces atherosclerotic plaque size and changes plaque composition [24]. Meanwhile, DCs have driven T cell immunity to promote atherosclerosis [25], which is enhanced by modified LDL but not native LDL [26]. Furthermore, proatherosclerotic LDL may form a positive feedback loop with Creaction protein (CRP) and LOX-1 to cause endothelia dysfunction which leads to atherosclerosis [27].…”

Tolerization against atherosclerosis using heat shock protein 60

“…T cells from atherosclerotic lesions from rabbits do also give strong proliferative response to mbHSP65 (Xu et al 1993a, b). Furthermore, oxLDL and LDLx (human group X-secreted phospholipase A2) but not native LDL can activate plaque T cells through DCs and HSP60 and 90 seem to play a role in this immune reactivity as T cell antigens (Liu et al 2015). This congruence a strong indication that these hHSP60 epitopes recognized already by early lesional T cells plays a pathogenic role throughout atherogenesis and may represent interesting early candidates for investigation in diagnostic, preventive, and therapeutic approaches; however, this needs further investigations with larger cohorts of patients.…”