Abstract
Regulatory T cells (Tregs) express the lineage-defining transcription factor FoxP3 and play crucial roles in self-tolerance and immune homeostasis. Thymic tTregs are selected based on affinity for self-antigens and are stable under most conditions. Peripheral pTregs differentiate from conventional CD4 T cells under the influence of TGF-β and other cytokines and are less stable. Treg plasticity refers to their ability to inducibly express molecules characteristic of helper CD4 T cell lineages like T-helper (Th)1, Th2, Th17 or follicular helper T cells. Plastic Tregs retain FoxP3 and are thought to be specialized regulators for “their” lineage. Unstable Tregs lose FoxP3 and switch to become exTregs, which acquire pro-inflammatory T-helper cell programs. Atherosclerosis with systemic hyperlipidemia, hypercholesterolemia, inflammatory cytokines, and local hypoxia provides an environment that is likely conducive to Tregs switching to exTregs.
Highlights
Atherosclerosis is the leading cause of death globally, with about 610,000 deaths in the US annually.Atherosclerosis is a chronic progressive inflammatory disease with an autoimmune component [1].Two recent clinical trials (CANTOS and COLCOT) show that anti-inflammatory therapies can have beneficial effects for outcomes of atherosclerosis, including myocardial infarction, cardiovascular death, and stroke [2,3]
Tregs are a largely stable lineage, recent studies have shown that the Treg program is mutable and that Tregs can lose their function, along with their lineage-marker (Foxp3), to form pathogenic exTregs
Emerging evidence indicates that atherosclerotic Apoe−/− mice have non-suppressive Th1-like Tregs [42] and that Tregs can convert to pathogenic Tfh and Th1 and Th17-like cells under atherosclerotic conditions [109,110]
Summary
Atherosclerosis is the leading cause of death globally, with about 610,000 deaths in the US annually. PTregs are typically found in mucosal tissues and are responsible for damping local inflammation elicited by foreign antigens [11,12,13,14] Both tTregs and pTregs maintain self-tolerance and suppress the activity of CD4+ CD25− Tcons via IL-10 and TGF-β production and through cell–cell interactions. Another subset of peripherally induced CD4+ Tregs, Cells 2020, 9, 2665; doi:10.3390/cells9122665 www.mdpi.com/journal/cells. TTregs and pTregs, but not Th3 or Tr1 cells, express the Forkhead box P3 (Foxp3) transcription factor. In mice, their phenotype is CD4+ CD25+ Foxp3+.
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