Frequency and Characterization of Tregs in Atherosclerosis

Regulatory T cells (Tregs) form an important T-cell subclass that provides protection against autoimmunity and may be used for treatment of autoimmune-like disorders, such as atherosclerosis. Various subsets of Tregs exist, but the best-characterized are CD4FoxP3CD25CD127 cells that comprise 5% to 10% of the CD4 T cells in human blood, lymphoid tissue, and epithelial barrier tissues. A significant fraction of these CD4 Tregs develops in the thymus and are called natural or thymic Tregs. The transcription factor Helios is reported to be exclusively expressed in thymic Tregs although this has been disputed. Tregs exert their immunosuppressive function mainly through secretion of the inhibitory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β, and cell–cell contact, mediated by membrane-bound TGF-β, cytotoxic T lymphocyte-associated antigen (CTLA-4), and glucocorticoid-induced tumor necrosis factor receptor familyrelated protein. In addition to the natural Tregs, CD4 Tregs differentiate from naïve CD4 T cells in secondary lymphoid organs and are called adaptive or peripheral Tregs, which include CD4FoxP3CD25CD127 cells with a similar phenotype to natural Treg, as well as IL-10–producing T regulatory type 1 cells, TGF-β–producing T helper-3 cells, and CD8Foxp3 Tregs. The importance of Tregs in modulation of immune responses in atherosclerosis has been demonstrated in several studies in mice where Tregs were partially or entirely depleted. LDLr mice lacking CD28 or CD80/CD86, costimulatory molecules that are essential for Treg development and homeostasis, show decreased Treg numbers associated with an increase in atherosclerosis, and treatment of ApoE mice with a Treg depleting CD25-specific antibody (PC61) aggravates lesion development. The contribution of Foxp3 Tregs to atherosclerosis development was first elucidated by a partial depletion of Foxp3 Tregs using a dendritic cell (DC)–based vaccination that provoked cytotoxic T-cell responses against Foxp3-expressing cells leading to enhanced atherosclerosis. Recently, Klingenberg et al 14 showed that a specific depletion of Foxp3 Tregs using DEREG/LDLr mice increases atherosclerosis development 2.1-fold. The focus of this review will be on the development of experimental therapies to increase the frequency of Tregs to reduce atherosclerosis and on their potency as a new immunetherapy to treat cardiovascular disease.