Interleukin-7 and interleukin-15 drive CD4+CD28null T lymphocyte expansion and function in patients with acute coronary syndrome

Cardiovasc Res. 2021 Jul 7;117(8):1935-1948. doi: 10.1093/cvr/cvaa202.


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-1β, 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-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.

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.

Keywords: Atherosclerosis; CD28null T cells; Cytokines; Inflammation; T lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / immunology*
  • Acute Coronary Syndrome / metabolism
  • Aged
  • CD28 Antigens / deficiency*
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Cytotoxicity, Immunologic / drug effects
  • Female
  • Humans
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-15 / pharmacology*
  • Interleukin-7 / pharmacology*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 3 / metabolism
  • Lymphocyte Activation / drug effects*
  • Male
  • Middle Aged
  • Phenotype
  • Phosphorylation
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism


  • CD28 Antigens
  • IFNG protein, human
  • IL15 protein, human
  • IL7 protein, human
  • Interleukin-15
  • Interleukin-7
  • STAT5 Transcription Factor
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • JAK1 protein, human
  • JAK3 protein, human
  • Janus Kinase 1
  • Janus Kinase 3