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.

Statins Induce the Accumulation of Regulatory T Cells in Atherosclerotic Plaque

“…It has been shown that Tregs prevent atherosclerosis via TGF-β signaling and Tregs do not relieve the progression of atherosclerosis and inflammatory response if Tregs fail to respond to TGF-β signaling (15,32). Increased concentration of TGF-β and IL-10 was associated with suppressing pathogenic inflammatory responses, regulating immunity and promoting atherosclerotic plaque stabilization (33). On the contrary, deletion of TGF-β or IL-10 signaling accelerates atherosclerosis and plaque vulnerability (34,35).…”

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

“…Activated TCRab + CD4 + cells constitute the dominant T lymphocyte population in vascular lesions and are mainly of the Th1 cell type. Natural regulatory T cells (Tregs) or induced peripheral Tregs efficiently inhibit experimental atherosclerosis development in several experimental models, whereas Treg depletion aggravates plaque formation (4). Accordingly, immune-mediated inflammation in atherosclerosis has been initially envisioned as solely orchestrated by T cells.…”

Immune Monitoring of Kidney Recipients: Biomarkers to Appreciate Immunosuppression -Associated Complications

“…These Th2 cells favor atherosclerotic plaque disruption/instability (Taleb et al, 2010a), a late event in atherosclerosis (Hansson, 2005). Induced Treg (iTreg), already described in Fig.2, protect mice from atherosclerosis and thus are anti-atherogenic (in yellow) (Mallat et al, 2003). Natural Treg -directly produced in the thymus− exert the same anti-atherogenic effect (Ait-Oufella et al, 2006).…”