Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.

Despite a growing interest in CD4 ϩ CD25 ϩ regulatory T cells (T reg ) that play a major role in self-tolerance and immunoregulation, fundamental parameters of the biology and homeostasis of these cells are poorly known. Here, we show that this population is composed of two T reg subsets that have distinct phenotypes and homeostasis in normal unmanipulated mice. In the steady state, some T reg remain quiescent and have a long lifespan, in the order of months, whereas the other T reg are dividing extensively and express multiple activation markers. After adoptive transfer, tissue-specific T reg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens. These results reveal the existence of a cycling T reg subset composed of autoreactive T reg that are continuously activated by tissue self-antigens.