Foxp3+CD4+ Regulatory T-Cell Subtypes and Atherosclerosis
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Atherosclerosis is initiated by accumulation of low-density lipoproteins in the intima of large arteries with inflammation largely driven by cells of the innate and adaptive immune system. Early studies indicated the presence of large numbers of T cells in all stages of lesion development—early lesions, fibrous plaques, and more advanced complex lesions, with many activated T cells secreting interferon-γ (IFN-γ).1 T cells present in mouse and human atherosclerotic lesions include invariant NKT (natural killer T) cells, cytotoxic CD8+ T cells, and CD4+ T cells. CD4+ T cells can be subdivided into multiple subtypes including Th1, Th2, Th17, follicular CD4+ T (Tfh) cells, and regulatory T cells, largely based on their patterns of cytokine secretion and the transcription factors they express. Th1 cells express the transcription factor Tbet, Th2 cells GATA3, Th17 cells RORγt, Tfh cells Bcl6, and the majority of CD4+ regulatory T cells express Foxp3.2 In atherosclerotic lesions, the majority of proatherogenic CD4+ T cells exhibit a Th1 profile producing high levels of IFN-γ, which activates monocytes, macrophages, and dendritic cells and inhibits the proliferation of vascular smooth muscle cells and their ability to produce collagen.3 Tfh cells are also proatherogenic,4 whereas the role of Th2 cells is more complex but can be protective5; the significance of Th17 cells in atherosclerosis remains to be elucidated.
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CD4+Foxp3+ regulatory T cells (Tregs) are also present in atherosclerotic lesions6 and have major roles in controlling immunologic tolerance and immune homeostasis. They are derived from the thymus but can also be induced in the periphery and require Foxp3 for their suppressive effects. Foxp3 is highly conserved in humans and mice, and it is Foxp3 protein expression levels rather than Treg numbers that is the major factor influencing the magnitude of Treg-suppressive effects. …