Low Levels of Circulating CD4+FoxP3+ T Cells Are Associated With an Increased Risk for Development of Myocardial Infarction But Not for Stroke

Abstract

Objective— Regulatory T cells (Tregs) protect against atherosclerosis in experimental models, but their association with cardiovascular disease in humans remains to be elucidated. The aim of the present study was to determine whether circulating Tregs predict the development of acute cardiovascular events in humans. Methods and Results— The study cohort consisted of a random sample of participants (n=700), aged 68 to 73 years, from the Malmö Diet and Cancer Study. Mononuclear leukocytes, stored at −140 ○ C at the baseline investigation in 1991–1994, were thawed and Tregs, defined by the expression of FoxP3 in CD4+ T cells, were analyzed by flow cytometry. There was no detectable loss of cells during storage, and the viability of thawed leukocytes was 95%. A low fraction of both CD4+FoxP3+ and CD4+CD25+FoxP3+ T cells was associated with a higher release of proinflammatory cytokines from activated mononuclear leukocytes, and this association was strongest for CD4+FoxP3+ cells. Eighty-four coronary events and 66 strokes were registered during follow-up until December 31, 2008. In a Cox proportional hazard regression model adjusting for major risk factors, low levels of baseline CD4+FoxP3+ T cells were associated with an increased risk for the development of acute coronary events but not stroke. There were no associations between CD4+CD25+FoxP3+ T cells and development of an acute coronary event or stroke. Conclusion— This study provides prospective evidence for the role of Tregs in the development of myocardial infarction. The findings are in accordance with previous experimental studies and provide clinical support for a protective role of Tregs in atherosclerosis. The lack of association between Tregs and stroke may reflect the more heterogeneous cause of this disease.

Human Carotid Plaques With High Levels of Interleukin-16 Are Associated With Reduced Risk for Cardiovascular Events

“…25 This could give a potential explanation for the beneficial effect of high IL-16 levels in dampening the T-cell response, and thereby the inflammatory drive in the plaque. Many previous studies have shown the beneficial role of Tregs in atherosclerosis, 5,26 and the correlation between IL-16 levels at the site of the inflamed plaque with FoxP3 expression could hold the key to the fewer atherosclerotic manifestations displayed in the group with higher level of IL-16. It remains to be seen whether and how IL-16-mediated T-cell recruitment directly affects plaque stability.…”

Regulatory/Effector T-Cell Ratio Is Reduced in Coronary Artery Disease

“…13-15, 20 Wigren et al defined Treg as CD4 + FoxP3 + or CD4 + CD25 + FoxP3 + cells and showed that there was an association between low baseline CD4 + FoxP3 + T cells and an increased risk for the development of acute coronary events but not stroke. 15 Their study was the first large-volume and long follow-up study investigating the association between circulating Treg, defined as the expression of FoxP3 in CD4 + T cells, and CAD, and suggests that Treg may play a protective role in human atherosclerosis and therefore are of potential clinical importance. Although the staining method using the Foxp3 molecule can discriminate between Treg and Teff more precisely than that using the combination of CD25 and CD127 molecules, it is possible that such a population may still include some Teff.…”

“…Some studies investigated the correlation between circulating Treg level and CAD to clarify whether impaired function or reduced numbers of Treg may contribute to the progression of atherosclerotic diseases in humans, but the results are still controversial. [13][14][15] Discrepancy among previous reports with regards to the association between circulating Treg level and CAD may potentially be due to the difference in immune system between humans and mice, or limitations in methodology. The transcription oronary artery disease (CAD) is one of the life-threatening manifestations of atherosclerosis in humans.…”

Foxp3 + Regulatory T Cells Play a Protective Role in Angiotensin II–Induced Aortic Aneurysm Formation in Mice

“…[9][10][11] We and others have shown the contribution of reduced Treg levels to the progression of human coronary artery disease. 12,13 Recently, CD4 + CD25 + Treg deficiency caused by genetic disruption of CD80/CD86 or CD28 costimulatory molecules has been shown to promote the development and rupture of angiotensin II-induced AAA in C57BL/6 wild-type mice, 14 suggesting a crucial role for endogenous CD4 + CD25…”