Decreased Naive and Increased Memory CD4+ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis

Abstract

BackgroundAdaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.Methods and FindingsWe examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI)) = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β = 0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].ConclusionsThese results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.

Reduced T-Cell Thymic Export Reflected by sj-TREC in Patients with Coronary Artery Disease

“…Previous studies also have demonstrated that significant reduction of Treg cells in NSTACS patients resulted both from the reduced export of RTE-Treg and accelerated apoptosis of Treg in the periphery 21) . In this study, the result that reduced sj-TREC copy number from total T lymphocytes in CAD patients was consistent with the previously reported reduced proportion of naïve T cells 13) . And the proportion of naïve T cells was ever used to reflect thymic output 48) .…”

“…Aging is associated with an alteration of the proportion of naïve T and effector memory T cells (Tem) in periphery 54) , with Tem expanding to maintain T cell homeostasis. Previous investigations have also reported a similar phenomenon in human and animal models of atherosclerosis 13,55) . Numerous factors have been involved in the immune system imbalance, the most important being thymus involution and the resultant decreased output of naïve T cells 54) .…”

“…Reduction of recent thymic emigration (RTE) and consequently lopsided T cell homeostasis can trigger some kind of autoimmune diseases, such as rheumatoid arthritis (RA), in experimental models [9][10][11][12] . In previous studies, investigators assessed output naïve T cells to determine whether T cell homeostasis regulated by continuous thymic export was impaired in patients with CAD 13) . Evidence from these investigations confirmed that atherogenesis is associated with altered T lymphocyte homeostasis.…”

Human Cytomegalovirus (HCMV)-Specific CD4 + T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

“…There is a body of evidence that in individuals over the age of 65 years there are changes to the immune response that increase the rates of morbidity and mortality in response to infection and autoimmune disease (38,39). Analysis of a number of large population cohorts recruited for cancer, dementia, and nutritional studies in the UK and the United States has shown a significant association between CMV seropositivity and mortality from cardiovascular-related disease (40)(41)(42)(43). Despite these observations, older CMV-seropositive individuals do not appear to suffer from overt HCMV disease from reactivating virus or superinfection, suggesting that the HCMV-specific T cells retain the ability to control the virus (44).…”

Stabilization of high-risk plaques

“…In contrast to Th 1, Tregs can suppress inflammatory responses by various mechanisms (182)(183)(184)(185)(186). Tregs serve to maintain immunological tolerance and suppress effector T cell responses (187). The atheroprotective effect of Tregs on atherosclerosis has been reported in both a mouse model and a human study (188,189).…”