ABSTRACT
AIMS: Inflammation has important roles in atherosclerosis. CD4+CD28null (CD28null) T cells are a specialized T lymphocyte subset that produce inflammatory cytokines and cytotoxic molecules. CD28null T cells expand preferentially in patients with acute coronary syndrome (ACS) rather than stable angina and are barely detectable in healthy subjects. Importantly, ACS patients with CD28null T-cell expansion have increased risk for recurrent acute coronary events and poor prognosis, compared to ACS patients in whom this cell subset does not expand. The mechanisms regulating CD28null T-cell expansion in ACS remain elusive. We therefore investigated the role of cytokines in CD28null T-cell expansion in ACS. METHODS AND RESULTS: High-purity sorted CD4+ T cells from ACS patients were treated with a panel of cytokines (TNF-α, IL-1ß, IL-6, IL-7, and IL-15), and effects on the number, phenotype, and function of CD28null T cells were analysed and compared to the control counterpart CD28+ T-cell subset. IL-7- and IL-15-induced expansion of CD28null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1ß, and IL-6 did not. The mechanisms underlying CD28null T-cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28null T cells compared to control CD28+ T cells. Additionally, IL-7/IL-15 markedly augmented CD28null T-cell cytotoxic function and interferon-γ production. Further mechanistic analyses revealed differences in baseline expression of component chains of IL-7/IL-15 receptors (CD127 and CD122) and increased baseline STAT5 phosphorylation in CD28null T cells from ACS patients compared to the control CD28+ T-cell subset. Notably, we demonstrate that CD28null T-cell expansion was significantly inhibited by Tofacitinib, a selective JAK1/JAK3 inhibitor that blocks IL-7/IL-15 signalling. CONCLUSION: Our novel data show that IL-7 and IL-15 drive the expansion and function of CD28null T cells from ACS patients suggesting that IL-7/IL-15 blockade may prevent expansion of these cells and improve patient outcomes.
Subject(s)
Acute Coronary Syndrome/immunology , CD28 Antigens/deficiency , CD4-Positive T-Lymphocytes/drug effects , Cell Proliferation/drug effects , Inflammation/immunology , Interleukin-15/pharmacology , Interleukin-7/pharmacology , Lymphocyte Activation/drug effects , Acute Coronary Syndrome/metabolism , Aged , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Cytotoxicity, Immunologic/drug effects , Female , Humans , Inflammation/metabolism , Interferon-gamma/metabolism , Janus Kinase 1/metabolism , Janus Kinase 3/metabolism , Male , Middle Aged , Phenotype , Phosphorylation , STAT5 Transcription Factor/metabolism , Signal Transduction , Tumor Necrosis Factor-alpha/metabolismABSTRACT
There has been much recent research into the therapeutic use of stem and progenitor cells for various diseases. Alongside this, there has also been considerable interest in the normal roles that endogenous precursor cells may play in both physiological and pathological settings. In the present review, we focus on two types of progenitor cell which are of potential relevance to vascular homoeostasis, namely the EPC (endothelial progenitor cell) and the smooth muscle progenitor cell. We discuss evidence for their existence and sources in adults, and the various techniques currently used to identify these cells. We examine data obtained from studies using different methods of progenitor identification and relate these to each other, in order to provide a framework in which to interpret the literature in this area. We review evidence for the influence of these vascular progenitor cells upon vascular function and the development and progression of atherosclerosis.
