ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells.
Endothelial cells (EC) play a central role in inflammatory immune responses and efficiently induce effector functions in T cells, despite lacking the classical costimulatory ligands CD80 and CD86. By using the mAb HIL-131 we now demonstrate that human inducible costimulator-ligand (ICOS-L), a molecule related to CD80/CD86, is constitutively expressed on human EC in vivo. In vitro, ICOS-L expression was strongly enhanced on human umbilical vein EC and microvascular EC by the inflammatory cytokines tumor necrosis factor alpha and IL-1beta, and to a lower extent by stimulation of EC by CD40 or lipopolysaccharide. Coculture of MHC class II(+) EC with resting memory CD4(+) T cells in the presence of superantigen led to a marked up-regulation of ICOS on T cells and to the production of Th1 (IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-10, IL-13). When these cocultures were performed in the presence of the inhibitory mAb HIL-131, secretion of all cytokines was reduced by about 50-80%, indicating that ICOS-L is a major costimulator in EC-mediated T cell activation. Taken together, our data suggest an important physiological role of ICOS-L in the reactivation of effector/memory T cells on the endothelium controlling the entry of immune cells into inflamed tissue.
Khayyamian
Saman
S
Molecular Immunology, Robert Koch-Institute, Nordufer 20, D-13353 Berlin, Germany.
Hutloff
Andreas
A
Büchner
Kerstin
K
Gräfe
Michael
M
Henn
Volker
V
Kroczek
Richard A
RA
Mages
Hans W
HW
D017398:Alternative Splicing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis* / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D011506:Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D016207:Cytokines; C556692:ICOS protein, human; C498514:ICOSLG protein, human; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007375:Interleukin-1; D018793:Interleukin-13; D007376:Interleukin-2; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma