Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cellsin vitro

Abstract

The role of costimulatory molecules other than CD80/CD86 in endothelial cell (EC)-dependent CD8(+) T cell activation including the generation of a distinct subset of endothelium-specific CTL (EC-CTL) remains unclear. Inducible costimulator (ICOS) and its ligand (ICOSL) are new members of the CD28 family mediating effector T cell differentiation and graft rejection in animal models. In this study endothelial ICOSL expression/regulation and effects on CD8(+) T cell allo-activation were analyzed. Constitutive expression of ICOSL was found on human EC. IL-1alpha and TNF-alpha induced ICOSL in an NF-kappaB-dependent manner on human umbilical vein endothelial cells (HUVEC). ICOS receptor was not detected on resting CD8(+) T cells but was induced in co-cultures with HUVEC. ICOSL blockade reduced CD8(+) T cell proliferation by 70% along with a marked decrease of IL-2 and IFN-gamma production in co-cultures with HUVEC. IL-2 supplementation of co-cultures could overcome the effect of ICOSL blockade; similarly the generation of EC-CTL was not impaired by ICOSL blockade in an IL-2-containing system. In vivo, weak constitutive ICOSL expression was found on coronary microvessels, which was significantly up-regulated during acute cardiac allograft rejection (p=0.04). Our data indicate a distinct role for ICOSL in EC-mediated CD8(+) T cell costimulation with implications for human cardiac allograft rejection.

Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development

“…It is important to note, however, that the role of NF-κB in ICOSL gene regulation appears to vary among different cell types. Previous studies have suggested that canonical NF-κB stimuli, such as IL-1 and TNF-α, induce the expression of ICOSL in endothelial cells and fibroblasts (35)(36)(37). Our findings suggest that LPS is inefficient in the induction of ICOSL expression in B cells.…”

Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development

“…It is important to note, however, that the role of NF-κB in ICOSL gene regulation appears to vary among different cell types. Previous studies have suggested that canonical NF-κB stimuli, such as IL-1 and TNF-α, induce the expression of ICOSL in endothelial cells and fibroblasts (35)(36)(37). Our findings suggest that LPS is inefficient in the induction of ICOSL expression in B cells.…”

The Brain Microvascular Endothelium Supports T Cell Proliferation and Has Potential for Alloantigen Presentation

“…ICOSL, a B-7 co-stimulatory family member was upregulated on HBECs following cytokine stimulation. Moreover, ICOSL has been shown previously to be a major co-stimulator in Human umbilical vein EC-mediated T cell activation, particularly in the re-activation of effector/memory T cells [12], [26]. Another co-stimulatory molecule, CD40, was constitutively expressed on HBEC and upregulated after IFNγ stimulation (Fig.…”

Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium

“…In this study we investigated the roleof the recently discovered moleculeLIGHT,also belonging to the TNFsuperfamily, in the interaction between activatedplatelets and transfectedcells (P3xTB.A7 cells) 26 were performed. By RT-PCR analysis, upregulation (2-3-fold) of IL-8, tissue factor and ICAM-1 waso bservedb yr ecombinant, monomerics CD40 whereas stimulation with cells overexpressing CD40L on the cell surface (P3xTB.A7) induced am arkedlys tronger upregulation of these cytokines (100-150-fold).E quivalent results were obtainedb yf lowc ytometrya fter 24 h( data not shown).D irect quantitative comparison is impossible becauseofthe lowstimulatoryefficiencyofsoluble CD40 as describedbefore (27) and the significant basal expression of LIGHT on the cell surfaceof non-transfectedP3x63Ag.8 cells whichwere used as anegative control.…”

Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development

“…It is important to note, however, that the role of NF-κB in ICOSL gene regulation appears to vary among different cell types. Previous studies have suggested that canonical NF-κB stimuli, such as IL-1 and TNF-α, induce the expression of ICOSL in endothelial cells and fibroblasts (35)(36)(37). Our findings suggest that LPS is inefficient in the induction of ICOSL expression in B cells.…”

The Brain Microvascular Endothelium Supports T Cell Proliferation and Has Potential for Alloantigen Presentation

“…ICOSL, a B-7 co-stimulatory family member was upregulated on HBECs following cytokine stimulation. Moreover, ICOSL has been shown previously to be a major co-stimulator in Human umbilical vein EC-mediated T cell activation, particularly in the re-activation of effector/memory T cells [12], [26]. Another co-stimulatory molecule, CD40, was constitutively expressed on HBEC and upregulated after IFNγ stimulation (Fig.…”

Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium

“…In this study we investigated the roleof the recently discovered moleculeLIGHT,also belonging to the TNFsuperfamily, in the interaction between activatedplatelets and transfectedcells (P3xTB.A7 cells) 26 were performed. By RT-PCR analysis, upregulation (2-3-fold) of IL-8, tissue factor and ICAM-1 waso bservedb yr ecombinant, monomerics CD40 whereas stimulation with cells overexpressing CD40L on the cell surface (P3xTB.A7) induced am arkedlys tronger upregulation of these cytokines (100-150-fold).E quivalent results were obtainedb yf lowc ytometrya fter 24 h( data not shown).D irect quantitative comparison is impossible becauseofthe lowstimulatoryefficiencyofsoluble CD40 as describedbefore (27) and the significant basal expression of LIGHT on the cell surfaceof non-transfectedP3x63Ag.8 cells whichwere used as anegative control.…”

Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development

“…It is important to note, however, that the role of NF-κB in ICOSL gene regulation appears to vary among different cell types. Previous studies have suggested that canonical NF-κB stimuli, such as IL-1 and TNF-α, induce the expression of ICOSL in endothelial cells and fibroblasts (35)(36)(37). Our findings suggest that LPS is inefficient in the induction of ICOSL expression in B cells.…”

The Brain Microvascular Endothelium Supports T Cell Proliferation and Has Potential for Alloantigen Presentation

“…ICOSL, a B-7 co-stimulatory family member was upregulated on HBECs following cytokine stimulation. Moreover, ICOSL has been shown previously to be a major co-stimulator in Human umbilical vein EC-mediated T cell activation, particularly in the re-activation of effector/memory T cells [12], [26]. Another co-stimulatory molecule, CD40, was constitutively expressed on HBEC and upregulated after IFNγ stimulation (Fig.…”

Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium

“…In this study we investigated the roleof the recently discovered moleculeLIGHT,also belonging to the TNFsuperfamily, in the interaction between activatedplatelets and transfectedcells (P3xTB.A7 cells) 26 were performed. By RT-PCR analysis, upregulation (2-3-fold) of IL-8, tissue factor and ICAM-1 waso bservedb yr ecombinant, monomerics CD40 whereas stimulation with cells overexpressing CD40L on the cell surface (P3xTB.A7) induced am arkedlys tronger upregulation of these cytokines (100-150-fold).E quivalent results were obtainedb yf lowc ytometrya fter 24 h( data not shown).D irect quantitative comparison is impossible becauseofthe lowstimulatoryefficiencyofsoluble CD40 as describedbefore (27) and the significant basal expression of LIGHT on the cell surfaceof non-transfectedP3x63Ag.8 cells whichwere used as anegative control.…”