High Levels of Costimulatory Receptors OX40 and 4-1BB Characterize CD4 ⁺ CD28 ^null T Cells in Patients With Acute Coronary Syndrome

Abstract

Rationale:Patients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4 ؉ CD28 null T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function. The mechanisms that govern CD4 ؉ CD28null T cell function are unknown.Objective: Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4 ؉ CD28 null T cells in ACS. Methods and Results: Expression of alternative costimulatory receptors (inducible costimulator, OX40, 4 -1BB,cytotoxic T lymphocyte associated antigen-4, programmed death-1) was quantified in CD4 ؉ CD28 null T cells from circulation of ACS and stable angina patients. Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4 ؉ CD28null T cells compared to classical CD4 ؉ CD28 ؉ T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4؉ CD28 null T cells constituted an important proportion of CD4 ؉ T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4 ؉ CD28null T cells to produce interferon-␥ and tumor necrosis factor-␣ and release perforin. Key Words: atherosclerosis Ⅲ coronary disease Ⅲ immune system Ⅲ lymphocytes Ⅲ receptors C oronary artery disease continues to be the leading cause of death in the developed world. Recent research has demonstrated that coronary artery disease results from an uncontrolled immune response and T lymphocytes have a central role in the development and progression of the disease. 1,2 Detailed analysis of CD4 ϩ T cells in coronary artery disease unveiled an increased frequency of a distinctive subset of lymphocytes called CD4 ϩ CD28 Conclusions: Costimulatory pathways are altered in CD4؉null T cells. 3 These cells are characterized by the lack of CD28, the main costimulatory receptor that regulates the response of T lymphocytes to antigen. 4 The CD4 ϩ CD28null T cell subset is present in low frequencies in healthy individuals and has also been shown to increase in patients with chronic inflammatory diseases such as autoimmunity. 5 In coronary artery disease, the frequency of CD4 The proinflammatory features of CD4 ϩ CD28 null T lymphocytes are surprising, as the activation and survival of T cells depends on costimulatory signals delivered via the CD28 receptor. 4 The activation of T cells requires not only the recognition of antigen, but also a second signal delivered by the interaction of the CD28 costimulatory receptor on T cells with its ligands on antigen presenting cells. 4 CD28 signaling controls the expression of interleukin-2 receptors and the production of interleukin-2 by activated T cells, which enable their proliferation, differentiation into effectors and survival. 12 Indeed, in th...

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

“…A proatherogenic effect has been demonstrated for CD80, CD86, and CD252 (136,137,139) as well as for CD137, a costimulatory receptor expressed on T lymphocytes (138,140). Human CD4 + CD28 null T cells, which are associated with ACS, express high levels of the costimulatory receptors CD134 and CD137 compared with conventional CD4 + CD28 + T cells, and in vitro studies show that the ligands for these receptors can costimulate these T cells (141).…”

“…Blocking Abs specific for CTLA-4 or PD-1 are both being used to enhance T cell-mediated antitumor responses in cancer patients (153). Therapeutic blockade of TNF/TNFR superfamily members such as the OX40 ligand/OX40 pathway may be effective for inhibiting CD4 + CD28 -T cells in the setting of ACS (141). In addition, B cell-depletion strategies are being investigated as well, and their impact on B-2 and B-1 cells and on CVD needs to be determined.…”

Increased Soluble CD137 Levels and CD4+ T‐Cell‐Associated Expression of CD137 in Acute Atherothrombotic Stroke

“…Moreover, CD28– T cells were shown to produce the cytotoxic molecules perforin and granzyme B, which resulted in cytolysis of the endothelium in vitro 29, 30. CD4+CD28– T cells have been found in patients with cerebrovascular and cardiovascular diseases such as acute coronary syndrome27, 31 and stroke 32, 33, 34. Of note, in these patients this proinflammatory cytokine production is upregulated by the costimulatory receptors OX40 and CD137 on circulating CD4+CD28– T cells,25 which were also found to be located in atherosclerotic plaques preferentially accumulating in unstable lesions 35.…”

“…In the CD137‐deficient atherosclerotic vessels of ApoE − / − CD137 − / − mice, crosslinking CD137L activation with soluble CD137 protein ex vivo activated CD137L signaling and led to the release of proinflammatory cytokines, such as TNF‐α and monocyte chemotactic protein‐1 (MCP‐1) 11. In ACS patients, blocking the CD137 pathway in vitro remarkably reduced the production of TNF‐α and IFN‐γ from circulating CD4+CD28– T cells, which were reported to induce rupture of atherosclerotic plaques by direct cytolysis of arterial smooth muscle and endothelial cells 27, 30. In our serial study, despite an irregular change of lymphocyte counts in the stroke patients, CD137 expression in the CD4+ and CD4+CD28– T cells displayed a decreasing trend at 3 and 14 days posttreatment with statin, a well‐known cholesterol‐lowering drug with multiple antiinflammatory properties 36.…”

Effect of Intensive Atorvastatin Therapy on Periprocedural PTEN Expression in CD4+T Lymphocytes of Patients with Unstable Angina Undergoing Percutaneous Coronary Intervention

“…The Atorvastatin for Reduction of Myocardial Damage during Angioplasty (ARMYDA) trial demonstrated that intensive atorvastatin could reduce PMI in patients undergoing PCI, and it is hypothesized that the favorable clinical prognosis associated with intensive statin therapy results from an anti-inflammatory effect mediated by these agents [2][3][4]. Plaque rupture can occur following PCI, and may induce both a local and systemic inflammatory response that is accompanied by the release of inflammatory factors for leukocyte and platelet activation (e.g., TNF-α, IL-6) [5][6][7]. Phosphatase and tension homolog deleted on chromosome ten (PTEN) has been identified as a tumor-suppressor gene and has been associated with maintaining the balance between cell survival and cell death, and which has been shown to inhibit an inflammatory response.…”