Abstract

AIMS: Inflammation has important roles in atherosclerosis. CD4+CD28null (CD28null) T cells are a specialised 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-1β, IL-6, IL-7, 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-1β 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. CONCLUSIONS: 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. TRANSLATIONAL PERSPECTIVE: CD28null T cells expansion in ACS patients is an independent predictor of future acute coronary events and poor prognosis. The precise mechanisms underlying CD28null T cell expansion in ACS remain elusive. We show that IL-7 and IL-15 cytokines cause expansion of CD28null T cells from ACS patients by triggering activation and proliferation, and augment the cytotoxic function of these cells and production of inflammatory cytokines. We demonstrate that CD28null T cell expansion is inhibited by Tofacitinib that specifically blocks IL-7/IL-15 signalling. Further dissection of the roles of IL-7/IL-15 may lead to more effective and specific anti-inflammatory therapies in ACS.