title: Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor.
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.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr, San Diego, CA 92121, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishimoto
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Hong
authors.forename: Karen G
authors.initials: KG
authors.lastname: Potter
authors.forename: Mari
authors.initials: M
authors.lastname: Maeda-Yamamoto
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation; D008407:Mast Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; D012333:RNA, Messenger; D017455:Receptors, IgE; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma; D002118:Calcium