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.
Copyright 2004 The American Association of Immunologists, Inc.
MeSH terms
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Animals
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Antibodies, Monoclonal / metabolism
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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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Antigens, CD / physiology*
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Antigens, Differentiation, B-Lymphocyte / biosynthesis
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism*
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B7-1 Antigen / biosynthesis
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Biomarkers
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CD27 Ligand
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Cell Cycle / immunology
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Cell Differentiation / immunology
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Cells, Cultured
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Cross-Linking Reagents / metabolism
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Growth Inhibitors / genetics
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Growth Inhibitors / immunology
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Growth Inhibitors / metabolism
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Growth Inhibitors / physiology
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Humans
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Immunoglobulin G / biosynthesis
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Ligands
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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MAP Kinase Signaling System / immunology
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitogen-Activated Protein Kinase Kinases / physiology
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Phosphatidylinositol 3-Kinases / physiology
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Plasma Cells / cytology
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Plasma Cells / immunology
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Plasma Cells / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation, B-Lymphocyte
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B7-1 Antigen
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Biomarkers
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CD27 Ligand
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CD70 protein, human
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Cd70 protein, mouse
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Cross-Linking Reagents
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Growth Inhibitors
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Immunoglobulin G
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Ligands
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Membrane Proteins
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Mitogen-Activated Protein Kinase Kinases