Abstract
The B7/CD28 family has profound modulatory effects in immune responses and constitutes an important target for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homologue (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells. Repetitive antigenic exposure, however, induces a complete loss of CD28H on many T cells, and CD28H negative T cells have a phenotype of terminal differentiation and senescence. After extensive screening in a receptor array, a B7-like molecule, B7 homologue 5 (B7-H5), was identified as a specific ligand for CD28H. B7-H5 is constitutively found in macrophages and could be induced on dendritic cells. The B7-H5/CD28H interaction selectively costimulates human T-cell growth and cytokine production via an AKT-dependent signalling cascade. Our study identifies a novel costimulatory pathway regulating human T-cell responses.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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B7 Antigens
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CD28 Antigens / chemistry
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CD28 Antigens / metabolism*
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Coculture Techniques
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Epitopes / immunology
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Fluoresceins / metabolism
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Gene Expression Regulation / drug effects
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Genome, Human / genetics
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HEK293 Cells
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Humans
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Ligands
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Molecular Sequence Data
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Protein Binding / drug effects
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Succinimides / metabolism
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Vanadates / pharmacology
Substances
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5-(6)-carboxyfluorescein diacetate succinimidyl ester
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B7 Antigens
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CD28 Antigens
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Epitopes
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Fluoresceins
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Ligands
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Membrane Proteins
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Succinimides
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TMIGD2 protein, human
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VSIR protein, human
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pervanadate
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Phosphotyrosine
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Vanadates