Activation of Dengue Virus-Specific T Cells Modulates Vascular Endothelial Growth Factor Receptor 2 Expression

Abstract

Background The pathogenic mechanisms underlying the increased vascular permeability in dengue hemorrhagic fever (DHF) are not well understood. Enhanced cellular immune activation, especially activation of serotype-cross reactive T cells, has been implicated in plasma leakage in DHF. Changes in several biological markers and mediators including cytokines, chemokines, angiogenic factors and their receptors have been shown to correlate with disease severity. A decline in plasma levels of a soluble form of vascular endothelial growth factor receptor 2 (VEGFR2), a receptor of vascular endothelial growth factor (VEGF), has been associated with plasma leakage in dengue patients. Objective We aimed to investigate the effect of dengue virus (DV)-specific CD8+ T cells on the expression of VEGFR2 on endothelial cells. Method An in vitro model was developed in which dengue virus-specific CD8+ T cells generated from peripheral blood mononuclear cells (PBMCs) of DHF patients were co-cultured with antigen-presenting cells, human umbilical vein endothelial cells (HUVECs) and activated with DV non-structural protein 3 (NS3) peptides. The expression of VEGFR2 by endothelial cells was measured. Results DV-specific CD8+ T cells were serotype cross-reactive. Activation of DV-specific CD8+ T cells resulted in down-regulation of soluble VEGFR2 production and an up-regulation of cell-associated VEGFR2. Conclusions Our findings indicate that activation of DV-specific T cell is associated with modulation of VEGFR2 expression that may contribute to increased VEGF responsiveness and vascular permeability.

Anticuerpos IgG4 específicos anti Aedes aegypti como factor protector en niños con dengue grave

“…También se identificaron niveles más bajos de vegf (53,3 ui/ml) en el dg, mientras que el vegfr2 fue más alto (10974,7 ui/ ml). Este resultado es consistente con los de Rattanamahaphoom y su equipo (30), quienes evidenciaron que la activación de células T específicas en el dg se asocia con la modulación de la expresión del vegfr2, que puede contribuir al aumento de la capacidad de respuesta del vegf y así estimular o conducir a la activación endotelial y fuga plasmática. Además, los niveles de vegf en pacientes con df no fueron significativamente diferentes de los del grupo de control con enfermedad febril no debida al dengue.…”

In vitro and in silico Models to Study Mosquito-Borne Flavivirus Neuropathogenesis, Prevention, and Treatment

“…Human PBMCs are a convenient source of human primary cells, because they can be obtained from both healthy volunteers and infected patients of all ages. These cells can also be used to study innate aspects of infection as well as the adaptive response to viral infection (Gunther et al, 2011; Correa et al, 2015; Rattanamahaphoom et al, 2017). In addition, dendritic cells, macrophages, and T cells can be derived from PBMCs for in vitro studies of the human immune response and host-pathogen interactions (Libraty et al, 2001; Reis et al, 2007; Wu et al, 2011; Gandini et al, 2013).…”

“…PBMCs are the most commonly used because human blood is a very convenient cell source that can be stored easily. Although PBMCs consist of a mixed population of blood leukocytes, they can also be used as a primary souce to futher purification of specific cell types (e.g., T cells, B cells) (Reis et al, 2007; Wu et al, 2011; Rawle et al, 2015; Zhang J. et al, 2016; Rattanamahaphoom et al, 2017).…”

“…Overall, in vitro models have proved to be a useful tool to study MBF, with examples that study virus molecular mechanisms (Correa et al, 2015; Londono-Renteria et al, 2017; Rattanamahaphoom et al, 2017), their implication in the inflammatory response (Lim et al, 2014; Duran et al, 2016), drug screening (Stolp et al, 2015; Wang L. F. et al, 2015; Sayce et al, 2016), or vaccine development (Nantachit et al, 2016, 2017; Kam et al, 2017). Thus, human cell-derived in vitro models could present a solution to modeling MBF infection and neuropathogenesis.…”