Abstract
Mast cells are the major effector-cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels on stimulation through the high-affinity receptor for immunoglobulin E (IgE; FcepsilonRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FcepsilonRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production on FcepsilonRI stimulation. Analysis of 4-1BB ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca2+ flux induced by FcepsilonRI stimulation. The defective Ca2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-gamma2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Antibodies, Monoclonal / immunology
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antigens, CD / metabolism*
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Calcium / pharmacology
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Cell Proliferation
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Cells, Cultured
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Cytokines / biosynthesis
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Cytokines / metabolism
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Gene Expression Regulation
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Mast Cells / cytology*
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Mast Cells / immunology
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Mast Cells / metabolism*
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Mice
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Mice, Knockout
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Phospholipase C gamma / metabolism
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Protein-Tyrosine Kinases / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, IgE / immunology*
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Receptors, IgE / metabolism
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Receptors, Nerve Growth Factor / deficiency
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Receptors, Nerve Growth Factor / genetics
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Receptors, Nerve Growth Factor / immunology
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Receptors, Nerve Growth Factor / metabolism*
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Receptors, Tumor Necrosis Factor / deficiency
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / immunology
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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src-Family Kinases / metabolism
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Cytokines
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RNA, Messenger
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Receptors, IgE
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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Tnfrsf9 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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lyn protein-tyrosine kinase
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src-Family Kinases
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Phospholipase C gamma
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Calcium