Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus

Giubilato, Simona; Liuzzo, Giovanna; Brugaletta, Salvatore; Pitocco, Dario; Graziani, Francesca; Smaldone, Costantino; Montone, Rocco Antonio; Pazzano, Vincenzo; Pedicino, Daniela; Biasucci, Luigi M.; Ghirlanda, Giovanni; Crea, Filippo

doi:10.1093/eurheartj/ehq499

Cited by 101 publications

(90 citation statements)

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“…[8][9][10] However, it remains unclear which specific subpopulation of T cells plays a major role in acute coronary syndrome. CD4 1 CD28 null T cells have been reported to contribute to acute coronary syndrome, 11,12 and expansion of CD4 1 CD28 null T cells is strongly associated with the recurrence of acute coronary events. 11 Furthermore, in diabetic patients, an increased frequency of CD4 1 CD28 null T cells correlated with poor outcome after an acute coronary event.…”

Section: Introductionmentioning

confidence: 99%

“…11 Furthermore, in diabetic patients, an increased frequency of CD4 1 CD28 null T cells correlated with poor outcome after an acute coronary event. 12 However, a role for CD8 1 T cells in human coronary artery disease has been identified less than for CD4 1 T cells. 13 The accumulation of CD28 null T cells is one of the most prominent changes during the immune aging process.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Youn

Lee

et al. 2014

Cell Mol Immunol

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Although T cells are known to be involved in the pathogenesis of coronary artery disease, it is unclear which subpopulation of T cells contributes to pathogenesis in acute myocardial infarction (MI). We studied the immunological characteristics and clinical impact of CD8 1 CD57 1 T cells in acute MI patients. The frequency of CD57 1 cells among CD8 1 T cells was examined in peripheral blood sampled the morning after acute MI events. Interestingly, the frequency of CD57 1 cells in the CD8 1 T-cell population correlated with cardiovascular mortality 6 months after acute MI. The immunological characteristics of CD8 1 CD57 1 T cells were elucidated by surface immunophenotyping, intracellular cytokine staining and flow cytometry. Immunophenotyping revealed that the CD8 1 CD57 1 T cells were activated, senescent T cells with pro-inflammatory and tissue homing properties. Because a high frequency of CD8 1 CD57 1 T cells is associated with short-term cardiovascular mortality in acute MI patients, this specific subset of CD8 1 T cells might contribute to acute coronary events via their pro-inflammatory and high cytotoxic capacities. Identification of a pathogenic CD8 1 T-cell subset expressing CD57 may offer opportunities for the evaluation and management of acute MI.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Youn

Lee

et al. 2014

Cell Mol Immunol

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“…6,9 In stark contrast to CD28 + T lymphocytes, CD28 null T cells release cytotoxic molecules (ie, perforin and granzymes) 6 that are instrumental in killing endothelial and vascular smooth muscle cells in vitro. 10 These properties suggest that CD28 null T cells have harmful effects in atherosclerosis, although a direct causal link is yet to be established, because this subset of T cells is present only in humans with an equivalent population absent in mice.…”

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confidence: 99%

Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 ⁺ CD28 ^null T Cells Resistant to Apoptosis in Acute Coronary Syndrome

et al. 2015

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709M yocardial infarction and stroke caused by atherosclerosis are the most frequent cardiovascular causes of death and disability in the world despite the progress in prevention and therapy.1 Recent evidence clearly implicates the innate and adaptive immune system in the pathogenesis of atherosclerosis.2 T lymphocytes, the main orchestrators of adaptive immune responses, have pivotal roles in atherosclerosis. In particular, proinflammatory CD4+ T lymphocytes such as T helper 1 cells have been shown to promote atherosclerosis in animal models and constitute the predominant T cells in human atherosclerotic plaques. [3][4][5] We and others have demonstrated that CD4 + CD28null T cells, a unique subset of T helper 1 lymphocytes characterized by the lack of costimulatory receptor CD28, are present in high numbers in the circulation and atherosclerotic plaques of patients with acute coronary syndrome (ACS), 6-8 but these cells are not present in healthy individuals. Moreover, CD4 + CD28null T cells (from now on abbreviated as CD28 null T cells) produce higher levels of inflammatory cytokines interferon-γ and tumor necrosis factor-α than conventional CD4 + CD28+ (CD28 + ) T cells. 6,9 In stark contrast to CD28 + T lymphocytes, CD28 null T cells release cytotoxic molecules (ie, perforin and granzymes) 6 that are instrumental in killing endothelial and vascular smooth muscle cells in vitro. 10 These properties suggest that CD28 null T cells have harmful effects in atherosclerosis, although a direct causal link is yet to be established, because this subset of T cells is present only in humans with an equivalent population absent in mice. Recently, we were the first to show that the distinguishing feature between CD28 null and conventional CD28 + T cells in ACS patients is a significantly higher expression on CD28 null T cells of alternative costimulatory receptors . We further demonstrated that 4-1BB and OX40 have critical roles in regulating the production of inflammatory cytokines interferon-γ and tumor necrosis factor-α and perforin release from CD28 null T cells in ACS. 6 In addition to their roles in T-cell costimulation, 4-1BB and OX40 are important for the survival of T cells. 11,12 As mentioned, ACS patients are known to harbor significantly higher numbers of CD28 null T cells in comparison with patients who have stable angina (SA) and healthy subjects. 8,13 Importantly, Background-The number of CD4 + CD28 null (CD28 null ) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28 null T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28 null T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28 null T cells in ACS. Methods and Results-We found that CD28null T cells in ACS were resistant to apoptosis induction...

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“…In fact, CD4 + CD28 null T-lymphocytes exert cytolitic effects on endothelial cells and express high levels of TNF-related apoptosis-inducing ligand (TRAIL), thus promoting smooth muscle cells apoptosis within the atherosclerotic plaque (Nakajima et al, 2002;Sato et al, 2006). With these premises, the recent finding of an expansion of CD4 + CD28 null T-cells in diabetic patients is extremely interesting, suggesting a possible role of adaptive immune disregulation, either primary or induced by the altered metabolic status and the inflammatory environment characterizing the disease, in the increased cardiovascular risk which is one of the most relevant clinical features of T2DM, accounting for the majority of disease-related mortality and morbidity (Giubilato et al, 2011). Consistently, in the same study CD4 + CD28 null T-lymphocytes expansion was closely related to a poor glycaemic control, and was associated with a higher incidence of cardiovascular events during followup.…”

Section: Diabetes and Adaptive Immunitymentioning

confidence: 99%

Type 2 Diabetes, Immunity and Cardiovascular Risk: A Complex Relationship

Pedicino¹,

Giglio²,

Galiffa³

et al. 2012

Pathophysiology and Complications of Diabetes Mellitus

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Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus

Abstract: In DM patients, CD4+CD28(null)T-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.

Cited by 101 publications

References 32 publications

Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 ⁺ CD28 ^null T Cells Resistant to Apoptosis in Acute Coronary Syndrome

Type 2 Diabetes, Immunity and Cardiovascular Risk: A Complex Relationship

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Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus

Abstract: In DM patients, CD4+CD28(null)T-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.

Cited by 101 publications

References 32 publications

Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 + CD28 null T Cells Resistant to Apoptosis in Acute Coronary Syndrome

Type 2 Diabetes, Immunity and Cardiovascular Risk: A Complex Relationship

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Product

Resources

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Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 ⁺ CD28 ^null T Cells Resistant to Apoptosis in Acute Coronary Syndrome