Abstract
Marginal zone (MZ) B cells mount rapid T-cell-independent (T-I) immune responses against microbial components such as LPS. While Toll-like receptor 4 (TLR4) is essential for LPS responses, MZ B cells uniquely express high levels of another LPS sensor Radioprotective 105 (RP105). However, little is known about how RP105 is used by MZ B cells. In this study, we investigated TLR4- or RP105-dependent MZ B cell responses by utilizing agonistic monoclonal antibodies (mAbs) to each receptor. Cross-linking TLR4 and RP105 at the same time with the mAbs induced robust IgM-secreting plasma cell generation as lipid A moiety of LPS. In contrast, stimulation with either mAb alone did not elicit such responses. RP105-deficient MZ B cells failed to produce IgM-secreting plasma cells in response to lipid A. TLR4 or lipid A stimulation of MZ B cells up-regulated their B lymphocyte-induced maturation protein 1 (Blimp-1) and X-box-binding protein 1 (Xbp-1) mRNA expression. RP105 stimulation alone did not give these responses and in fact decreased TLR4-mediated their expression. Compared with wild-type (WT) MZ B cells, RP105-deficient MZ B cells exhibited increased levels of Blimp-1 and Xbp-1 mRNA expression in response to lipid A. Lipid A or TLR4 plus RP105 stimulation induced massive proliferation and expression of Bcl-xL and c-Myc in WT but not RP105-deficient MZ B cells. These responses contributed to TLR4-mediated anti-apoptotic responses in MZ B cells. Thus, RP105 contributes in a unique way to the TLR4-dependent survival, proliferation and plasma cell generation of MZ B cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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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, Surface / genetics
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Antigens, Surface / immunology*
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Antigens, Surface / metabolism
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Blotting, Western
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cell Proliferation
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Gene Expression
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Immunoglobulin M / immunology
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Immunoglobulin M / metabolism
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Lipid A / pharmacology
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Lymphocyte Antigen 96 / genetics
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Lymphocyte Antigen 96 / immunology*
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Lymphocyte Antigen 96 / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / genetics
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Multiprotein Complexes / immunology
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Multiprotein Complexes / metabolism
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Plasma Cells / drug effects
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Plasma Cells / immunology*
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Plasma Cells / metabolism
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Proteins c-myc / immunology
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Proto-Oncogene Proteins c-myc / metabolism
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Regulatory Factor X Transcription Factors
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Reverse Transcriptase Polymerase Chain Reaction
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology*
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Toll-Like Receptor 4 / metabolism
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription Factors / metabolism
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X-Box Binding Protein 1
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bcl-X Protein / immunology
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bcl-X Protein / metabolism
Substances
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Antibodies
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Antigens, CD
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Antigens, Surface
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Bcl2l1 protein, mouse
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DNA-Binding Proteins
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Immunoglobulin M
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Lipid A
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Ly78 protein, mouse
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Ly86 protein, mouse
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Ly96 protein, mouse
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Lymphocyte Antigen 96
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Membrane Glycoproteins
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Multiprotein Complexes
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Myc protein, mouse
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Prdm1 protein, mouse
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Proto-Oncogene Proteins c-myc
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Regulatory Factor X Transcription Factors
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Transcription Factors
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X-Box Binding Protein 1
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Xbp1 protein, mouse
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bcl-X Protein
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Positive Regulatory Domain I-Binding Factor 1