Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cells in vitro.
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.
Klingenberg
Roland
R
Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
Autschbach
Frank
F
Gleissner
Christian
C
Giese
Thomas
T
Wambsganss
Nadine
N
Sommer
Natascha
N
Richter
Guenther
G
Katus
Hugo A
HA
Dengler
Thomas J
TJ
D000208:Acute Disease; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000502:physiology; D011506:Proteins / Q000032:analysis / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D014184:Transplantation, Homologous
D015703:Antigens, CD; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D016328:NF-kappa B; D011506:Proteins