Previous studies demonstrated that interleukin-10 (IL-10) overexpression decreases formation of early fatty-streak lesions in mice independent of lipoprotein levels. The present studies, using bone marrow transplantation, demonstrate that overexpression of IL-10 by T cells inhibits advanced atherosclerotic lesions in LDL receptor-null mice fed an atherogenic diet. In mice receiving bone marrow from the IL-10 transgenic mice compared with those receiving wild-type marrow, there was a 47% decrease in lesion size and a marked decrease in lesion complexity with an 80% reduction in the necrotic core. Accumulation of cholesterol and phospholipid oxidation products in the aorta was decreased by 50% to 80%, unrelated to plasma lipid or IL-10 levels. Our studies also provide insight into the mechanism of the IL-10-mediated decrease in lesion size. Although a strong influence toward a Th1 phenotype has previously been demonstrated in atherosclerotic models, T lymphocytes in the IL-10 transgenic (Tg) group revealed a marked shift to a Th2 phenotype, with decreased IFN-gamma production and an increase in IL-10. Evaluation of specific immunoglobulin subclasses demonstrated a preponderance of IgG(1) isotype, characteristic of a Th2 influence on B cell immunoglobulin class-switching in the IL-10 Tg group. A major finding of these studies was altered monocyte/macrophage function in the IL-10 Tg group. Monocytes showed a decrease in activation resulting in decreased expression of IFN-gamma. Furthermore, macrophage foam cells within lesions of the IL-10 Tg group exhibited markedly decreased apoptosis. These studies demonstrate that T lymphocyte IL-10 can influence the function of other immune cells to reduce the development of advanced atherosclerotic lesions in mice.