Interleukin-7 and interleukin-15 drive CD4(+)CD28(null) T lymphocyte expansion and function in patients with acute coronary syndrome

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.