T Helper Cell Infiltration and Foam Cell Proliferation Are Early Events in the Development of Atherosclerosis in Cholesterol-Fed Rabbits

Abstract

Abstract The involvement of T cells in the early cellular events in atherosclerosis was studied in rabbits fed a 1% cholesterol diet by use of specific monoclonal anti-rabbit CD5 and CD4 antibodies. T cells were not seen in the aortic intimas of rabbits not fed cholesterol but were seen in intimal lesions in cholesterol-fed rabbits. Accumulation of T cells in plaques occurred between 2 and 4 weeks after commencement of cholesterol feeding, and the greatest density of CD5-positive T cells was observed after 4 weeks (11.2±6.0 cells/mm 2 [mean±SEM]; P <.02 compared with normal control rabbits, P <.03 compared with 2-week plaques). Staining for CD4 indicated that the majority of these T cells were T helper cells (9.9±4.9 cells/mm 2 ). At this time, plaques showed a dense cellular infiltrate of macrophages (3623±467 cells/mm 2 ) and macrophage proliferation was evident (2.1±1.1% of total plaque cells). As the cross-sectional area of intimal lesions increased progressively in subsequent weeks, their cellularity declined (8 weeks, 2239±271 cells/mm 2 ; 12 weeks, 1535±55 cells/mm 2 ; 16 weeks, 1747±242 cells/mm 2 , P <.05 for all groups compared with the 4-week group). The density of the T cell infiltrate (8 weeks, 6.7±3.0 cells/mm 2 ; 12 weeks, 0.6±0.2 cells/mm 2 ; 16 weeks, 1.0±0.4 cells/mm 2 ) and the proliferative index of cells within plaques (8 weeks, 0.6±0.2%; 12 weeks, 0.8±0.3%; 16 weeks, 0.2±0.2%) also declined. Smooth muscle cell capping was observed in these later plaques without smooth muscle cell proliferation. These studies demonstrate that helper T cell infiltration into plaques is an early event in atherogenesis and is associated with local macrophage proliferation, suggesting a role for T cells in the initiation of atherosclerosis.