Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease

Abstract

ObjectiveRegulatory T cells (Tregs) are considered atheroprotective, and low levels have been associated with the acute coronary syndrome (ACS), particularly non‐ST elevation (NSTE)‐ACS. However, the functional properties as well as homeostasis of Tregs are mainly unknown in coronary artery disease (CAD). Here, we investigated the composition and functional properties of naïve (n) and memory (m)Tregs in patients with NSTE‐ACS and in patients 6–12 months post‐ACS.MethodsBased on the expression of CD25, FOXP3, CD127, CD45RA, CD39 and CTLA‐4, Treg subsets were defined by flow cytometry in whole blood or isolated CD4+ T cells. The functional properties of nTregs and mTregs were examined in terms of proliferative capacity and modulation of cytokine secretion. To understand the potential consequences of Treg defects, we also investigated correlations with lipopolysaccharide (LPS)‐induced cytokine secretion and ultrasound‐defined carotid atherosclerosis.ResultsBoth NSTE‐ACS and post‐ACS patients exhibited reduced levels of nTregs (P < 0.001) compared with healthy control subjects, but without compensatory increases in mTregs. Both nTregs and mTregs from patients showed significantly lower replicative rates and impaired capacity to modulate T‐cell proliferation and secretion of interferon‐gamma and IL‐10. The Treg defect was also associated with LPS‐induced cytokine secretion and increased burden of carotid atherosclerosis.ConclusionOur results demonstrate a functional and homeostatic Treg defect in patients with NSTE‐ACS and also in stabilized patients 6–12 months after ACS. Moreover, this defect was associated with a subclinical proinflammatory and atherogenic state. We believe that the failure to preserve Treg function and homeostasis reflects a need for immune‐restoring strategies in CAD.

The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart

“…Unstable plaques have increased levels of Th1, NK, and CTL cells and decreased levels of anti-inflammatory regulatory T (Treg) cells [ 31 ]. Recent studies show that the relative levels of Treg cells are reduced and their functionality is impaired in patients with CAD [ 32 , 33 ]. Knockout of CXCL10 in the apolipoprotein E-deficient mouse model of atherosclerosis was associated with increased Treg cell numbers and activity, along with a reduction in lesion formation [ 34 ].…”

Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome

“…It has been revealed that an abnormal quantity or dysfunction of Tregs might be associated with many different conditions, including carcinoma [ 6 ], diabetes [ 7 ], organ transplant reactions [ 8 ], systemic autoimmune disorders [ 9 ], and CAD [ 10 – 12 ]. A few studies have shown that a downregulation in Tregs might contribute to the development of ACS [ 11 , 12 ], although others have reported conflicting results, some describing an upregulation of Tregs in patients with ACS [ 13 – 15 ], and others suggesting no significant finding in patients with ACS [ 16 , 17 ]. Meanwhile, the definition of Treg marker patterns has long been controversial.…”

Immune checkpoint proteins: exploring their therapeutic potential to regulate atherosclerosis

“…There is limited information on CTLA‐4 in cardiovascular patients. One study describes reduced circulating Treg numbers and function in both patients with non‐ST elevation acute coronary syndrome and in stabilized patients (6–12 months after ACS) in comparison with healthy subjects (Hasib et al, ). Interestingly, within this Treg population, CTLA‐4 + cells were increased, possibly to compensate for the decreased number and function of Tregs in the periphery.…”