Dickkopf-3 acts as a modulator of B cell fate and function

Julia Ludwig; Giuseppina Federico; Sandra Prokosch; Günter Küblbeck; Sabine Schmitt; Alexandra Klevenz; Hermann-Josef Gröne; Lars Nitschke; Bernd Arnold

doi:10.4049/jimmunol.1402160

Dickkopf-3 acts as a modulator of B cell fate and function

J Immunol. 2015 Mar 15;194(6):2624-34. doi: 10.4049/jimmunol.1402160. Epub 2015 Feb 11.

Authors

Julia Ludwig¹, Giuseppina Federico², Sandra Prokosch³, Günter Küblbeck³, Sabine Schmitt³, Alexandra Klevenz³, Hermann-Josef Gröne², Lars Nitschke⁴, Bernd Arnold³

Affiliations

¹ Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany; [email protected].
² Division of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany; and.
³ Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany;
⁴ Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany.

PMID: 25672757
DOI: 10.4049/jimmunol.1402160

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Apoptosis / genetics
Apoptosis / immunology
Autoantibodies / immunology
Autoantibodies / metabolism
B-Lymphocytes / immunology*
B-Lymphocytes / metabolism
Calcium / immunology
Calcium / metabolism
Cell Proliferation*
Cell Survival / genetics
Cell Survival / immunology
Cells, Cultured
Cytokines / immunology
Cytokines / metabolism
Flow Cytometry
Gene Expression / immunology
Humans
Intercellular Signaling Peptides and Proteins / deficiency
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / immunology*
Lectins / genetics
Lectins / immunology
Lectins / metabolism
Lupus Erythematosus, Systemic / genetics
Lupus Erythematosus, Systemic / immunology
Lupus Erythematosus, Systemic / metabolism
Lymphocyte Count
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Mice, Knockout
Receptors, Antigen, B-Cell / genetics
Receptors, Antigen, B-Cell / immunology
Receptors, Antigen, B-Cell / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sialic Acid Binding Immunoglobulin-like Lectins
Signal Transduction / genetics
Signal Transduction / immunology*

Substances

Adaptor Proteins, Signal Transducing
Autoantibodies
Cytokines
Dkk3 protein, mouse
Intercellular Signaling Peptides and Proteins
Lectins
Receptors, Antigen, B-Cell
Sialic Acid Binding Immunoglobulin-like Lectins
Siglecg protein, mouse
Calcium