Abstract
B7h, expressed by several cell types, binds ICOS expressed by activated T cells. We have previously shown that B7h triggering by ICOS-Fc inhibits human endothelial cell adhesiveness. This work investigated the effect of ICOS-Fc on human monocyte-derived dendritic cells (DCs). We found that DCs matured with LPS in the presence of ICOS-Fc (mDCs(ICOS)) produced greater amounts of IL-23 and IL-10, and promoted a higher secretion of IL-17A and IL-17F in MLCs than did those DCs matured with LPS alone (mDCs). Moreover, mDCs(ICOS) pulsed with the keyhole limpet hemocyanin Ag during the maturation phase were better stimulators of Ag-specific MHC class I-, but not class II-restricted T cells than mDCs. This was probably due to promotion of cross-presentation because it was not detected when the Flu-MA(58-66) Ag was directly loaded on already matured DCs and mDCs(ICOS). Finally, ICOS-Fc inhibited the adhesion of both immature DCs and mDCs to vascular and lymphoid endothelial cells, their migratory activity, and the expression of the Rac-1 activator β-Pix involved in cell motility. These data suggest that B7h stimulation modulates DC function with effects on their maturation and recruitment into tissues. This opens a novel view on the use of interactors of the ICOS:B7h system as immunomodulatory drugs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigen Presentation / drug effects
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Cell Adhesion / drug effects
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Cell Differentiation / drug effects
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Cell Movement / drug effects
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Cells, Cultured / cytology
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Cells, Cultured / immunology
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Dendritic Cells / cytology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Guanine Nucleotide Exchange Factors / biosynthesis
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Guanine Nucleotide Exchange Factors / genetics
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HLA-A2 Antigen / immunology
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Hemocyanins / pharmacology
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Human Umbilical Vein Endothelial Cells / cytology
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Humans
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Immunoglobulin Fc Fragments / immunology
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Immunoglobulin G / immunology
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Inducible T-Cell Co-Stimulator Ligand / immunology*
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Inducible T-Cell Co-Stimulator Protein / genetics
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Inducible T-Cell Co-Stimulator Protein / immunology*
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Inducible T-Cell Co-Stimulator Protein / metabolism
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Lymphocyte Culture Test, Mixed
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Monocytes / cytology
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Recombinant Fusion Proteins / pharmacology
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction / drug effects
Substances
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ARHGEF7 protein, human
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Guanine Nucleotide Exchange Factors
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HLA-A2 Antigen
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ICOS protein, human
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ICOSLG protein, human
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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Inducible T-Cell Co-Stimulator Ligand
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Inducible T-Cell Co-Stimulator Protein
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Lipopolysaccharides
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Recombinant Fusion Proteins
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Rho Guanine Nucleotide Exchange Factors
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lipopolysaccharide, E coli O55-B5
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Hemocyanins
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keyhole-limpet hemocyanin