Induction of Dendritic Cell–Mediated Activation of T Cells From Atherosclerotic Plaques by Human Heat Shock Protein 60

BACKGROUND Atherosclerosis is characterized by the presence of activated immune-competent cells including dendritic cells (DCs) and T cells, dead cells, and oxidized low-density lipoprotein. HSP60 (Heat shock protein 60) has been implicated in atherosclerosis. A plasma protein, Annexin A5, has atheroprotective properties. METHODS AND RESULTS Human DCs differentiated from peripheral blood monocytes were treated with human HSP60 or HSP90 and autologous T cells were cocultured with these pretreated DCs (mDCs). HSP60 induced mDCs and T-cell activation as determined by FACScan (Fluorescence associated cell scan), gene-activation, and cytokine production. HSP60-induced T-cell activation was partly major histocompatibility complex class II-dependent. T cells exposed to HSP60-treated mDCs produced interferon-γ, interleukin-17, but not transforming growth factor-β. HSP60 did not promote expression of Toll-like receptors 2 or 4. HSP90 promoted mDCs maturation but had no effect on T-cell activation. Annexin A5 inhibited HSP60-proinflammatory Th1/Th17 effects on mDCs and T cells, and partly bound HSP60. Further, Annexin A5 inhibited HSP-induced activation of mDCs and also oxidized low-density lipoprotein-induced HSP-production from mDCs. Experiments on mDCs and T cells derived from carotid atherosclerotic plaques from patients with symptomatic carotid disease gave similar results as from blood donors. CONCLUSIONS HSP60 induces mDCs activation and partly major histocompatibility complex class II-dependent activation of blood- and plaque-derived T cells, which is mostly of Th1/Th17 type. HSP60 could thus be an important T-cell antigen in plaques, and also mediate oxidized low-density lipoproteins immunogenic effects on DC-T-cell activation, promoting plaque rupture and clinical manifestations of cardiovascular disease. Annexin A5 inhibits both oxidized low-density lipoprotein-induced HSP60, and HSP60-mediated immune activation, which suggests a potential therapeutic role.