P728CD4+CD28 null T cells are enriched at the culprit lesion site in STE-ACS and promote NET production

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Abstract

Purpose: ST-elevation acute coronary syndrome (STE-ACS) is among the leading causes of death. Acute coronary atherothrombosis as the underlying event is still poorly understood. We hypothesized that circulating leukocytes adhere to atherosclerotic plaques and mediate thrombotic occlusion. It has been shown that circulating CD4+CD28null T-cells, which release high levels of granzyme B and perforin, are increased in STE-ACS, especially in patients suffering from diabetes and/or recurrent cardiovascular events. Neutrophil extracellular traps (NETs) released by activated polymorphonuclear neutrophils (PMNs) have been shown to be a crucial component in thrombogenesis. We characterized CD4+CD28null cells at the culprit lesion site in STE-ACS patients and tested their impact on NET formation.

Methods: We included 150 STE-ACS patients who underwent primary percutaneous coronary intervention (PCI) at the Vienna General Hospital. Culprit site blood and solid thrombus material were collected during thrombectomy. In parallel, a blood sample from the femoral arterial sheath was collected. Flow cytometry was employed to measure CD4+CD28null T cells in whole blood and solid thrombus specimens. Granzyme B and perforin levels were determined in plasma by ELISA technique. Isolated PMNs were stimulated with granzyme B and/or PMA, and NET formation was assessed by immunohistochemistry.

Results: CD4+CD28null T cells were increased at the culprit lesion site both in coronary whole blood and the solid thrombus, compared with peripheral blood (n=106, p<0.0001, 7.79±9.68 vs. 9.92±11.44% of CD4+ cells; n=20, p<0.01, 8.14±10.08 vs. 13.6±14.12% of CD4+ cells). Perforin and granzyme B were decreased in coronary CD4+CD28null T cells and correlated inversely with granzyme B levels in culprit site plasma. Granzyme B induced netosis of PMNs in vitro.

Conclusion: Granzyme B/Perforin-releasing CD4+CD28null T cells accumulate at the culprit lesion site in STE-ACS, and may directly induce netosis. Further experiments will evaluate the significance of this finding in the pathogenesis of acute coronary syndromes.

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