Naturally occurring regulatory T cells: recent insights in health and disease.

Development of naturally occurring CD4+CD25+ T regulatory cells (Treg) in the thymus requires the transcription factor Foxp3. Major histocompatibility complex (MHC) class II, self-ligands expressed by epithelial cells, and thymic stromal lymphopoietin also appear to play important roles. In addition, several molecular regulators of T-cell receptor (TCR) signaling (both positive and negative) have been implicated in the control of Treg development. Foxp3 is a transcriptional repressor of IL-2 and other cytokines and appears to maintain the anergic and suppressor function of these cells. Multiple cell types (T cells, B cells, dendritic cells [DC], and natural killer [NK] cells) are targeted by Treg using diverse suppressor mechanisms, whereas factors that regulate Treg proliferation and function, including Toll-like receptor (TLR) ligands, have also been identified. Because Treg play an important role in the control of autoimmunity, therapeutic strategies are being pursued to enhance their numbers and function in specific autoimmune diseases. In transplantation, where Treg also offer potential for therapy of rejection and graft-versus-host disease (GVHD), indirect allorecognition may be the dominant pathway for immune regulation by these cells. In tumor immunology, Treg have emerged as major suppressors of T-cell-mediated antitumor responses and represent a significant obstacle to effective anticancer vaccines. Strategies aimed at depletion/functional inhibition of these cells by molecular targeting must maintain a critical balance between tumor immunity and self-tolerance.