title: CD19 regulates innate immunity by the toll-like receptor RP105 signaling in B lymphocytes.
abstract: Lipopolysaccharide (LPS) is a major gram-negative bacterial component that stimulates innate immune response and also induces B-lymphocyte activation. Recent studies have revealed that common molecular patterns of microorganisms such as LPS are recognized by toll-like receptors (TLRs). B cells have 2 known TLRs that mediate LPS signaling, TLR4 and RP105 (CD180). While TLR4 is expressed on immune cells of various types, RP105 is preferentially expressed on mature B cells. Here we demonstrate that CD19 plays a major role in regulating signal transduction through RP105. Anti-RP105 ligation induced normal proliferation of B cells from mice deficient for MyD88, an adaptor protein that mediates most TLR pathways. By contrast, the loss of CD19 resulted in modest B-cell proliferation against anti-RP105 stimulation as well as LPS stimulation. LPS induced tyrosine phosphorylation of CD19, which was RP105-dependent but TLR4-independent. CD19 formed a complex with Lyn and Vav following RP105 ligation, and CD19 expression was required for optimal Lyn activation and Vav phosphorylation. Consistently, B cells deficient for CD19 exhibited specific defect in the activation of c-Jun N-terminal kinases following RP105 ligation and LPS stimulation. In contrast, CD19 and phosphatidylinositol 3-kinase independently regulated intracellular calcium mobilization induced by anti-RP105 stimulation. Thus, signaling through the B-cell-specific LPS receptor RP105 is uniquely regulated by the B-cell-specific signaling component, Lyn/CD19/Vav complex.
authors.affiliation: Department of Regenerative Medicine, Research Institute, International Medical Center of Japan, Tokyo.
authors.forename: Norihito
authors.initials: N
authors.lastname: Yazawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Noriko
authors.initials: N
authors.lastname: Asano
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okochi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D018941:Antigens, CD19; D002352:Carrier Proteins; D008070:Lipopolysaccharides; C490500:Ly78 protein, mouse; D008562:Membrane Glycoproteins; D015513:Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D051567:Proto-Oncogene Proteins c-vav; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C496619:Vav1 protein, mouse; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium