title: Dickkopf-3 acts as a modulator of B cell fate and function.
abstract: The mechanisms responsible for the generation of a mature B1 and B2 cell compartment are still poorly understood. In this study, we demonstrated that absence of Dickkopf-3 (DKK3) led to changes in the composition of the B cell compartment, which were due to an altered development and maintenance program of B cells. Development of B2 cells was impaired at the pre- and immature B cell stage, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice. Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation behavior of B1 cells. DKK3 may act via the BCR signaling pathway, as Ca(2+) influx upon BCR stimulation was increased and SiglecG, a molecule shown to inhibit Calcium signaling, was downregulated in the absence of DKK3. DKK3-deficient mice exhibited altered Ab responses and an increased secretion of the cytokine IL-10. Additionally, DKK3 limited autoimmunity in a model of systemic lupus erythematosus. In summary, we identified DKK3 as a novel modulator interfering with B cell fate as well as the maintenance program of B cells, leading to changes in B cell immune responses.
authors: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany; j.ludwig@dkfz-heidelberg.de.
authors: Julia
authors: J
authors: Ludwig
authors: Division of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors: Giuseppina
authors: G
authors: Federico
authors: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors: Sandra
authors: S
authors: Prokosch
authors: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors: Günter
authors: G
authors: Küblbeck
authors: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors: Sabine
authors: S
authors: Schmitt
authors: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors: Alexandra
authors: A
authors: Klevenz
authors: Division of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors: Hermann-Josef
authors: HJ
authors: Gröne
authors: Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany.
authors: Lars
authors: L
authors: Nitschke
authors: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors: Bernd
authors: B
authors: Arnold
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D037102:Lectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D016207:Cytokines; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse; D002118:Calcium