Abstract 1734: Chemokine Receptor 7 Is Critically Involved In Low-density Lipoprotein Induced Atherosclerosis
Background: The chemokine receptor 7 (CCR7) on dendritic cells (DC) is required for cell migration to the secondary lymphoid organs in order to promote DC-dependent T-cell priming. Modification of low densitiy lipoprotein (LDL) to oxidized (ox)LDL is considered as a key event in atherogenesis whereas oxLDL acts as a predominant antigen. We here investigated the influence of CCR7-deficiency on oxLDL induced DC-dependent T cell priming and atheroscle-rotic plaque development, linking atherosclerosis to the adaptive immunity.
Methods: CCR7 −/− mice were cross-bred with LDLR−/− mice (ccr7−/−/ldlr−/−) and fed with a cholesterol rich diet for 12 weeks. Aortic plaque area was determined by en face Oil Red O staining. Plasma lipids and INFγ-levels were analyzed by ELISA. Bone marrow derived cell were differentiated into DC with GM-CSF. Following stimulation of DC with native (n) and oxLDL we analyzed CCR7 and MHC-II expression by RT-PCR and FACS analysis and migration towards CCL19 in a transwell-assay. OxLDL-dependent T-cell priming was analyzed in an antigen presentation assay and monitored by a proliferation assay and FACS-analysis in order to identify an oxLDL specific T-cell receptor. Additionally, we co-cultivated CCR7+/+ T-cells with oxLDL stimulated DCs and injected these T-cells into ccr7−/− /ldlr−/− -mice during feeding with a cholesterol rich diet.
Results: Atherosclerotic plaque formation and TH1-cytokine response was significantly reduced in the ccr7−/−/ldlr−/− mice. OxLDL but not nLDL promoted DC maturation, CCR7 and MHC-II expression and enhances DC migration. Furthermore, stimulation of DCs with oxLDL induced T-cell proliferation and expression of an oxLDL specific T-cell receptor V β 6. Additionally we could re-establish the atherosclerotic phenotype in ccr7−/−/ldlr−/− mice by the injection of CCR7+/+ T-cells, which were co-cultivated with oxLDL stimulated DCs.
Conclusion: CCR7 critically influences atherosclerotic plaque development by enabling oxLDL dependent T-cell priming by DCs in secondary lymph organs. Our data further imply that food derived LDL cholesterol initiated immune response drives atherosclerotic plaque development via CCR7.