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.…”

The Impact of Memory T Cells on Rejection and the Induction of Tolerance

“…Nonetheless, despite Tm having less of a requirement for CD80/86 and CD40 engagement, Tm may be dependent on other costimulatory pathways for the complete acquisition of effector function which may be potential targets for blockade (Table 1). For example the ICOS/ICOSL pathway has been implicated in both CD4 ϩ and CD8 ϩ memory responses (92,93). Also, 4 -1BB/4 -1BBL interactions have been shown to be important in CD8 ϩ T-cell recall responses (94,95) and it has been suggested that there may be a significant contribution of OX40/OX40L interactions in memory CD4 ϩ T-cell responses (95,96).…”

Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells – possible implications for the ICOS/ICOS-ligand axis in disease course and resolution

“…ICOS provides a positive signal to T cells by binding to its ligand (ICOS-L) on professional antigen-presenting cells (APCs) such as B cells, macrophages and dendritic cells (DCs) [14], as well as other cell types, including endothelial [15] and epithelial [16] cells. Initially, ICOS was shown to enhance the proliferation and differentiation of T cells via the induction of certain cytokines such as IL-4 [17], IL-5, interferon (IFN)-g and IL-10 [13].…”