title: The RP105/MD-1 complex is indispensable for TLR4/MD-2-dependent proliferation and IgM-secreting plasma cell differentiation of marginal zone B cells.
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.
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan. ynagai@med.u-toyama.ac.jp
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yanagibashi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikutani
authors.forename: Ai
authors.initials: A
authors.lastname: Kariyone
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Hirai
authors.forename: Masao
authors.initials: M
authors.lastname: Kimoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D008050:Lipid A / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000954:Antigens, Surface; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D008050:Lipid A; C490500:Ly78 protein, mouse; C113553:Ly86 protein, mouse; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; C489428:Myc protein, mouse; C513258:Prdm1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D000071701:Regulatory Factor X Transcription Factors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051020:bcl-X Protein; D000074462:Positive Regulatory Domain I-Binding Factor 1