• Daria Vdovenko, Carolina Balbi, Dario Di Silvestre, Giulia Passignani, Yustina M Puspitasari, Martina Zarak-Crnkovic, Pierluigi Mauri, Giovanni G Camici, Thomas F Lüscher, Urs Eriksson, and Giuseppe Vassalli.
• Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
• Eur. J. Clin. Invest. 2022 Jun 1; 52 (6): e13769.

BackgroundMicrovesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood.MethodsCD4+ T cells isolated from peripheral blood of healthy human donors were stimulated using anti-CD3/anti-CD28-coated beads. Proteomic profiling of microvesicles was performed using linear discriminant analysis (LDA) from activated T cells (MV.Act) and nonactivated T cells (MV.NAct). In addition, data processing analysis was performed using MaxQUANT workflow. Differentially expressed proteins found in MV.Act or MV.NAct samples with identification frequency = 100%, which were selected by both LDA (p < .01) and MaxQUANT (p < .01) workflows, were defined as "high-confidence" differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed.ResultsT cells released large amounts of microvesicles upon stimulation. Proteomic profiling of microvesicles using LDA identified 2279 proteins (n = 2110 and n = 851 proteins in MV.Act and MV.NAct, respectively). Protein-protein interaction network models reconstructed from both differentially expressed proteins (n = 594; LDA p ≤ .01) and "high-confidence" differentially expressed proteins (n = 98; p ≤ .01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organisation and TNFα-induced apoptosis. For instance, MV.Act were highly enriched with IFN-γ, a key proinflammatory pathway related to effector CD4+ T cells. Endothelial cell incubation with MV.Act induced superoxide generation, apoptosis, endothelial wound healing impairment and endothelial monolayer barrier disruption.ConclusionsT cell receptor-mediated activation of CD4+ T cells stimulates the release of microvesicles enriched with proteins involved in immune responses, inflammation and apoptosis. T cell-derived microvesicles alter microvascular endothelial function and barrier permeability, potentially promoting tissue inflammation.© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

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