Continuous Activation of Autoreactive CD4(+) CD25(+) Regulatory T Cells in the Steady State

Despite a growing interest in CD4(+) CD25(+) 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.