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

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-1α and TNF-α induced ICOSL in an NF-κB-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-γ 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. [ABSTRACT FROM AUTHOR]