Foxp3+ regulatory T cells (Tregs) are unique in their immunosuppressive abilities and contribution to immune regulation. However, the homeostatic processes and survival programs that maintain the Treg population remain unclear. Here, we highlight the recent study by Pierson et al., 1 which dissected the regulatory mechanisms of Treg homeostasis and survival. By utilizing transgenic models, the authors provide evidence to support the notion that peripheral Tregs are able to alter their proliferative and apoptotic rates to rapidly restore a numerical deficit through both interleukin 2 and costimulation-dependent pathways. Tregs are characterized by their capacity to modulate immune responses and can typically be identified by their specific expression of Foxp3, the transcription factor that endows T cells with their regulatory functions. 2, 3 Tregs are critical and indispensable for maintaining peripheral tolerance, and there is an active balance between regulatory and effective immune responses under the steady state. Indeed, deterioration of the balance between regulatory and effective immune responses can lead to the induction of several types of diseases. For instance, effective immune responses are often hindered by an excessive number of Tregs in the tumor microenvironment, 4 whereas decreases in the number and functionality of Tregs are observed in many autoimmune diseases and inflammatory conditions. 5–7 Given that Tregs are postulated to be valuable targets for immune therapies against tumor and autoimmune diseases, there is an urgent need to understand both the cellular and molecular mechanisms contributing to Treg homeostasis. Unlike effector T cells, Tregs are considered a group of anergic and quiescent cells, as supported by in vitro studies. 8 However, Tregs undergo homeostatic expansion and vigorous proliferation, particularly in a lymphopenic host, 9 suggesting that these cells are active under such circumstances and that an intact immune system may help to maintain Treg homeostasis and vice versa. Programmed cell death (apoptosis) is the predominant underlying mechanism for maintaining T cell homeostasis. 10, 11 The immune response against foreign antigens begins robustly with effector T-cell activation and proliferation, and the population of activated T cells is then restrained and controlled through apoptosis to circumvent an excessive immune response. Apoptosis itself is a delicate process that can be initiated via either an extrinsic or intrinsic signaling cascade. 12 The Bcl-2 protein family, including Bcl-2, Bcl-XL, Mcl-1, Blf-1 and A1, is composed of anti-apoptotic proteins that are able to suppress the activation of the apoptotic regulators Bax and Bak. Conversely, the anti-apoptotic Bcl-2 protein family can be antagonized by pro-apoptotic BH3-only proteins, including Bim, Bik, Puma and Bad. 13 In T cells, the dependence on apoptoticrelated proteins varies during different developmental stages. 14–17 The regulation of Treg homeostasis and survival has been dissected by a study recently reported in Nature Immunology by Pierson et al. These researchers utilized a transgenic model to study the cellular and molecular mechanisms that contribute to Treg population homeostasis. 1 5-bromo-2’-deoxyuridine (BrdU) was administrated to identify the proliferative profile of Tregs in vivo and to assess whether the Treg population is stable and quiescent. It was found that Tregs actually proliferate more rapidly than conventional T cells under a static condition, indicating that the Treg population is dynamic. By using transgenic female mice heterozygous for Thy1. 1 and DTR (diphtheria toxin receptor) in the Foxp3 locus of the …