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.