Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor |
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Authors: | Nishimoto Hajime Lee Seung-Woo Hong Hong Potter Karen G Maeda-Yamamoto Mari Kinoshita Tatsuya Kawakami Yuko Mittler Robert S Kwon Byoung S Ware Carl F Croft Michael Kawakami Toshiaki |
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Affiliation: | Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr, San Diego, CA 92121, USA. |
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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. |
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