title: Signaling through CD70 regulates B cell activation and IgG production.
abstract: CD70, the cellular ligand of the TNF receptor family member CD27, is expressed transiently on activated T and B cells and constitutively on a subset of B cell chronic lymphocytic leukemia and large B cell lymphomas. In the present study, we used B cells constitutively expressing CD70 to study the functional consequences of signaling through CD70. In vitro, CD70 ligation with anti-CD70 mAbs strongly supported proliferation and cell cycle entry of B cells submitogenically stimulated with either anti-CD40 mAb, LPS, or IL-4. In this process, the cell surface receptors CD25, CD44, CD69, CD95, and GL7 were up-regulated, whereas the expression of CD21, CD62L, surface IgM (sIgM), and sIgD was decreased. Addition of CD70 mAb to low dose LPS-stimulated CD70-positive B cells strongly diminished IgG secretion and enhanced production of IgM. Signaling through CD70 on B cells was dependent on the initiation of both PI3K and MEK pathways. In vivo exposure to either CD70 mAb or the CD70 counterreceptor CD27 down-regulated CD62L and sIgM on CD70-positive B cells. CD70 signaling during T cell-dependent immune responses also decreased IgG-specific Ab titers. Together, the in vitro and in vivo data demonstrate that CD70 has potent reverse signaling properties in B cells, initiating a signaling cascade that regulates expansion and differentiation.
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Nolte
authors.forename: Kiki
authors.initials: K
authors.lastname: Tesselaar
authors.forename: Bianca
authors.initials: B
authors.lastname: Heemskerk
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018122:B7-1 Antigen / Q000096:biosynthesis; D015415:Biomarkers; D053282:CD27 Ligand; D002453:Cell Cycle / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D006131:Growth Inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D018122:B7-1 Antigen; D015415:Biomarkers; D053282:CD27 Ligand; D003432:Cross-Linking Reagents; D006131:Growth Inhibitors; D007074:Immunoglobulin G; D008024:Ligands; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; C505771:CD70 protein, human; C505772:Cd70 protein, mouse