Endothelial Microparticles Interact with and Support the Proliferation of T Cells

Abstract

Endothelial cells (EC) closely interact with circulating lymphocytes. Aggression or activation of the endothelium leads to an increased shedding of EC microparticles (MP). Endothelial MP (EMP) are found in high plasma levels in numerous immunoinflammatory diseases, e.g. atherosclerosis, sepsis, multiple sclerosis and cerebral malaria, supporting their role as effectors and markers of vascular dysfunction. Given our recently described role for human brain microvascular endothelial cells (HBEC) in modulating immune responses we investigated how HBEC-derived MP could interact with and support the proliferation of T cells. Like their mother cells, EMP expressed molecules important for antigen presentation and T cell co-stimulation, i.e., β2-microglobulin, MHC II, CD40 and ICOSL. HBEC were able to take up fluorescently labeled antigens with EMP also containing fluorescent antigens suggestive of antigen carryover from HBEC to EMP. In co-cultures, fluorescently labeled EMP from resting or cytokine-stimulated HBEC formed conjugates with both CD4+ and CD8+ subsets, with higher proportions of T cells binding EMP from cytokine stimulated cells. The increased binding of EMP from cytokine stimulated HBEC to T cells was VCAM-1 and ICAM-1-dependent. Finally, in CFSE T cell proliferation assays using anti-CD3 mAb or T cell mitogens, EMP promoted the proliferation of CD4+ T cells and that of CD8+ T cells in the absence of exogenous stimuli and in the T cell mitogenic stimulation. Our findings provide novel evidence that EMP can enhance T cell activation and potentially ensuing antigen presentation, thereby pointing towards a novel role for MP in neuro-immunological complications of infectious diseases.

Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content

“…MP were prepared as previously reported67. Briefly, whole blood was centrifuged at 1,500 g for 15 min at room temperature to obtain platelet poor plasma (PPP).…”

Human Microglia Respond to Malaria-Induced Extracellular Vesicles

“…EVs derived from plasmodium-infected red blood cell (MiREVs) are immunogenic and can influence systemic inflammation [16]. They are also known to promote antigen presentation and T cell stimulation [6,16,17]. We have reported that MiREVs contain small regulatory human and plasmodial RNAs, which are readily transferred to various cell types, including human bone marrow-derived endothelial cells, implying their role in host-pathogen interactions [18].…”

Appearance of claudin-5+ leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles

“…In vivo analysis has shown elevated endothelial EV-leukocyte complexes in plasma from MS patients during disease exacerbation [42]. And binding of endothelial EVs, obtained from blood of patients with severe systemic inflammatory response syndrome, to neutrophils has been demonstrated in vitro [43], as has binding of EVs from BMEC cultures to both monocytes [44] and lymphocytes [45]. That inflammation in and outside the CNS [46–51], and adhesion of leukocytes [52], each triggers release of EVs from endothelial cells supports a juxtacrine mechanism for endothelial EVs to transfer junctional proteins to leukocytes at or near the BBB during neuroinflammatory disease.…”