Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E–Knockout Mice

Abstract

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 (10 6 cells per mouse) with their cognate antigen (50 μg 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-γ ( 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.