Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

Abstract

Cytotoxic lymphocytes encompass natural killer lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, natural killer (NK) T cells, γ, δ (γδ)-T cells and human CD4 + CD28À T cells.These cells play critical roles in inflammatory diseases and in controlling cancers and infections. Cytotoxic lymphocytes can be activated via a number of mechanisms that may involve dendritic cells, macrophages, cytokines or surface proteins on stressed cells. Upon activation, they secrete pro-inflammatory cytokines as well as anti-inflammatory cytokines, chemokines and cytotoxins to promote inflammation and the development of atherosclerotic lesions including vulnerable lesions, which are strongly implicated in myocardial infarctions and strokes. Here, we review the mechanisms that activate and regulate cytotoxic lymphocyte activity, including activating and inhibitory receptors, cytokines, chemokine receptors-chemokine systems utilized to home to inflamed lesions and cytotoxins and cytokines through which they affect other cells within lesions. We also examine their roles in human and mouse models of atherosclerosis and the mechanisms by which they exert their pathogenic effects. Finally, we discuss strategies for therapeutically targeting these cells to prevent the development of atherosclerotic lesions and vulnerable plaques and the challenge of developing highly targeted therapies that only minimally affect the body's immune system, avoiding the complications, such as increased susceptibility to infections, which are currently associated with many immunotherapies for autoimmune diseases. LINKED ARTICLESThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/ 10.1111/bcp.v82.4/issuetoc Abbreviation TCR, T cell receptor; MHC, major histocompablity complex; NKG2D, natural-killer group 2, member D; TRAIL, TNF-related apoptosis-inducing ligand; DNAM-1, DNAX accessory molecule-1; Clec9A, C-type lectin domain family 9 member A

Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death

“…T cells constitute a variable but substantial proportion of the immune cell population in the atherosclerotic plaque and are significant drivers of the inflammatory responses that underlie atherosclerosis 1 , 3 . CD4 + T cells are the predominant T cell subset in atherosclerotic lesions of Apolipoprotein E-deficient ( Apoe − / − ) mice.…”

Fas-positive lymphocytes are associated with systemic inflammation in obstructive sleep apnea syndrome

“…Tan et al found a high proportion of CD8+ cells and a low proportion of CD4+ cells according to the AHI in children suffering from OSAS [10]. CD8+ cells constitute the T cell subpopulation which contributes to the formation of atherosclerotic lesions [11]. We previously reported an elevated proportion of lymphocytes with Fas expression in patients with lung cancer and in COPD [12, 13].…”

Targeting inflammation to reduce cardiovascular disease risk

“…Their work is complemented by the review from Foks and Kuiper (), where the authors discuss the therapeutic potential to control atherosclerosis through targeting a large variety of co‐stimulatory and inhibitory immune checkpoint proteins. In addition, the role of cytotoxic lymphocytes such as NK cells, CD8 + T‐cells, NK T‐cells, γδ T‐cells and human CD4 + CD28 − T‐cells in the development of atherosclerosis and unstable atheromas is reviewed (Kyaw et al ., ).…”