Microvesicles released from activated CD4+ T cells alter microvascular endothelial cell function, 2022, Vdovenko et al

Abstract

Background
Microvesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood.

Methods
CD4+ 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 (MV.Act) and non-activated 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<0.01) and MaxQUANT (P<0.01) workflows, were defined as “high-confidence” differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed.

Results
T 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≤0.01) and “high-confidence” differentially expressed proteins (n=98; P≤0.01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organization, and TNFα-induced apoptosis. For instance, MV.Act were highly enriched with IFN-γ, a key pro-inflammatory 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.

Conclusions
T-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.

Open access, https://onlinelibrary.wiley.com/doi/10.1111/eci.13769