Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice

Background - T helper type 1 ( Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 ( Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis. Methods and Results - Clones of ovalbumin ( OVA) - specific Tr1 cells expanded in vitro were administered intraperitoneally ( 106 cells per mouse) with their cognate antigen ( 50 mug of OVA subcutaneously in complete Freund's adjuvant [CFA]) to female apolipoprotein E - knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA) + OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels ( P < 0.0001), a decrease in the production of interferon-gamma ( P < 0.001), and an increase in interleukin-10 production ( P < 0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A - stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA) + Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA) + Tr1 compared with controls ( P = 0.002 to P < 0.0001). Plaques of mice injected with (OVA/CFA) + Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice. Conclusions-Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.