Abstract 5157: Atherosclerotic Plaque Development Depends on T-cell Priming Within the Secondary Lymphatic Organs
Background: The chemokine receptor 7 (CCR7) is required for the migration of dendritic cells and T-cells to the secondary lymphoid organs (SLO) in order to promote DC-dependent T-cell priming. Here we investigated the influence of CCR7-deficiency on T-cell distribution in animals on cholesterol rich diet. In vitro, we analyzed whether oxLDL induced the expansion of a T-cell carrying a specific T-cell receptor subset and whether this T-cell receptor could be found in animals fed with a high cholesterol diet. Finally we investigated whether atherosclerosis can be reconstituted when ex vivo primed T-cells were given to CCR7-deficient mice while feeding with a cholesterol rich diet.
Methods and Results: T-cell number within the aorta was significantly increased, whereas T-cells within the SLO were reduced in ccr7−/−/ldlr−/− mice compared to ldlr−/−-mice as analyzed by CD3 staining of serial sections (immunhistochemistry, n=12–17). OxLDL (10μg/mL) but not nLDL (10μg/mL) promoted DC maturation in vitro (CCR7 and MHC-II expression, n=4) and in vivo (CD80 and CD86 expression, n=4) as monitored by FACS-analysis. To characterize an oxLDL specific T-cell, we co-cultivated nLDL and oxLDL stimulated DCs with T-cells and analyzed T-cell activation (BrdU, n=5), and the expression of an oxLDL specific T-cell receptor subset (real-time PCR, n=4). OxLDL but not nLDL stimulated DCs induced T-cell proliferation, which was accompanied with the expression of the T-cell receptor chains Vα10 and Vβ6. These T-cells could also be found within the aorta and the SLO of ldlr −/−-mice following feeding and was found to be significantly reduced in ccr7−/−/ldlr−/− mice as analyzed by T-cell receptor expression (real-time PCR and FACS-analysis, n=4–5). Finally, to investigate whether this specific T-cell is responsible for atherosclerotic plaque development, we injected oxLDL expanded T-ells into ccr7−/−/ldlr−/− mice while feeding with a cholesterol rich diet (1×107 cells) and observed a complete reconstitution of the atherosclerotic phenotype (en face preparation of oil red stained aortas, n=5–14),
Conclusion: Our results indicate that atherosclerotic plaque development is driven by an antigenic process induced by oxLDL and promoted by a specific T-cell.