Regulatory T-Cell Plasticity

During the past 2 decades, human and animals studies have clearly documented the crucial role of inflammation in the development and complications of atherosclerosis. Both innate immunity and adaptive immunity are involved in this process. The first evidence that suggested a role of adaptive immunity in atherosclerosis was the widespread detection of the major histocompatibility class II in human atherosclerotic plaques and the presence of a large amount of CD3 lymphocytes in human and mouse atherosclerotic lesions. Most of the T cells in mouse and human atherosclerotic plaques are CD4 T-helper (Th) cells expressing the αβ T-cell antigen receptor. Among CD4 T cells, Th1 cells have been shown to exert proatherogenic effects, whereas regulatory T cells (Tregs) display atheroprotective properties. The role of Th2 and Th17 cells is still debated. Helper T-cell subsets are defined by the production of cytokines or the expression of characteristic lineage-defining transcription factors. Th1 cells are generated on priming in the presence of interleukin (IL)-12 that promotes the expression of the transcription factor T-bet and stimulates the production of the Th1 prototypical cytokine interferon-γ (IFN-γ). Tregs have a central role in the dominant control of immunologic tolerance and maintenance of immune homeostasis. They were first identified in mice and later in humans. The transcription factor FoxP3 is essential for the generation and the functions of Tregs. FoxP3 deficiency leads to a multiorgan autoimmune disease as can be observed in the scurfy mouse and in hu man immune dysregulation, polyendocrinopathy, enteropathy X–linked syndrome patients. Natural or thymic FoxP3 Tregs acquire regulatory lineage commitment already on maturation in the thymus, whereas adaptive or peripheral FoxP3 Tregs can be induced from mature CD4 Th cells in the periphery under the influence of different stimulations, especially transforming growth factor-β. Other subsets of Tregs that do not express FoxP3 have been described. Type 1 regulatory T cells (Tr-1) are characterized by the production of large amounts of IL-10, a potent anti-inflammatory and antiatherosclerotic cytokine, and IL-10–dependent suppression of T-cell responses. In atherosclerosis, Tregs and Tr-1 cells exert protective effects. Significant acceleration of atherosclerosis has been observed in mice with reduced Treg cell numbers as obtained by invalidation of CD80/86, CD28, and ICOS (inducible T-cell costimulator) or after treatment with CD25-depleting antibodies. Other approaches for Treg cell depletion, including antisense-induced Treg cell apoptosis, vaccination of mice against FoxP3, or the use of mice expressing the diphtheria toxin receptor under control of the FoxP3 promoter, all concluded to increased vascular inflammation and atherosclerosis in the absence of Tregs. In contrast, adoptive transfer of CD4CD25 Treg cells or IL-10–producing Tr-1 cells reduced atherosclerotic lesion development in Apoe mice.