Interleukin-7 and interleukin-15 drive CD4+CD28null T lymphocyte expansion and function in patients with acute coronary syndrome. Issue 8 (9th July 2020)

• Record Type: Journal Article
• Authors: Bullenkamp, Jessica; Mengoni, Veronica; Kaur, Satdip; Chhetri, Ismita; Dimou, Paraskevi; Astroulakis, Zoë M J; Kaski, Juan Carlos; Dumitriu, Ingrid E
• Is Part Of: Cardiovascular research. Volume 117:Issue 8(2021)
• Page Start: 1935
• Page End: 1948
• Publication Date: 2020-07-09
• Subjects: Atherosclerosis -- Inflammation -- T lymphocytes -- CD28null T cells -- Cytokines; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvaa202
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Inflammation has important roles in atherosclerosis. CD4 + CD28 null (CD28 null ) T cells are a specialized T lymphocyte subset that produce inflammatory cytokines and cytotoxic molecules. CD28 null 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 CD28 null 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 CD28 null T-cell expansion in ACS remain elusive. We therefore investigated the role of cytokines in CD28 null 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-1β, IL-6, IL-7, and IL-15), and effects on the number, phenotype, and function of CD28 null T cells were analysed and compared to the control counterpart CD28 + T-cell subset. IL-7- and IL-15-induced expansion of CD28 null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1β, and IL-6 did not. The mechanisms underlying CD28 null T-cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28 null T cells compared to control CD28 + T cells. Additionally, IL-7/IL-15 markedly augmented CD28 null 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 CD28 null T cells from ACS patients compared to the control CD28 + T-cell subset. Notably, we demonstrate that CD28 null 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 CD28 null T cells from ACS patients suggesting that IL-7/IL-15 blockade may prevent expansion of these cells and improve patient outcomes. Graphical Abstract: