During initiation of immune responses, dendritic cells migrate from sites of antigen capture to the T cell zones of lymphoid organs to activate antigen-specific T cells. It remains to be determined whether dendritic cells that enter or develop within atherosclerotic plaques migrate from the plaques, and if so, whether T dependent immune responses that may thereby develop against plaque antigens lead to progression of atherosclerosis. In contrast to our incomplete state of knowledge regarding the role of dendritic cells and T cells in atherosclerosis, evidence that macrophages are involved in the initiation and progression of atherosclerotic lesions is quite strong. Monocytes are well known as the precursors for macrophages, but monocytes can also become dendritic cells in vitro, when cultured with specific exogenous cytokines or when cocultured with endothelial cells, and in vivo. In both human and mouse models, the capacity of monocyte-derived cells to leave tissues is associated with their development into dendritic cells, giving rise to the hypothesis that differentiation of monocytes into dendritic cells may favor their clearance from atherosclerotic plaques. Taking this view, development of dendritic cells from monocytes within the plaque would tend to promote regression. On the other hand, the migration of monocyte-derived dendritic cells from atherosclerotic plaques may favor the development of T-dependent immune responses that potentially mediate the progression of lesions. Our preliminary evidence indicates that monocyte-derived dendritic cell migration is impaired greatly in apoE-deficient mice, supporting the former hypothesis. In the present study, we will further characterize the status and function of dendritic cells in apoE- and LDL receptor-deficient mice. Then we will study whether monocyte and macrophage-derived cells migrate from atherosclerotic lesions during regression of plaques and what routes of migration they may take. The phenotype of any such migrating cells will be assessed, particularly with regard to whether emigrating cells have developed into dendritic cells. The significance of migration from the plaques will be investigated using apoE-/- mice that are deficient in molecules that mediate migratory clearance of dendritic cells from tissues. The long term goal of this work is to define how antigen presenting cells, particularly those derived from monocytes, participate in progression and regression of atherosclerosis, with a view toward understanding how manipulating the function of these cells may favor regressive disease.
