Fate and Function Dickkopf-3 Acts as a Modulator of B Cell

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. The Journal of Immunology , 2015, 194: 000–000. The

[1]  A. Rolink,et al.  The selection of mature B cells is critically dependent on the expression level of the co-receptor CD19. , 2014, Immunology letters.

[2]  T. Tedder,et al.  IL-10-producing regulatory B cells (B10 cells) in autoimmune disease , 2013, Arthritis Research & Therapy.

[3]  G. Chang,et al.  Zebrafish Dkk3a Protein Regulates the Activity of myf5 Promoter through Interaction with Membrane Receptor Integrin α6b* , 2012, The Journal of Biological Chemistry.

[4]  Elin Axelsson,et al.  Essential role of EBF1 in the generation and function of distinct mature B cell types , 2012, The Journal of experimental medicine.

[5]  G. Silverman,et al.  Protective Roles of Natural IgM Antibodies , 2012, Front. Immun..

[6]  H. Nakauchi,et al.  Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells , 2012, Proceedings of the National Academy of Sciences.

[7]  E. Montecino-Rodriguez,et al.  B-1 B cell development in the fetus and adult. , 2012, Immunity.

[8]  C. Niehrs,et al.  Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance , 2012, Proceedings of the National Academy of Sciences.

[9]  M. Hermann,et al.  Distinct expression patterns of dickkopf genes during late embryonic development of Danio rerio. , 2011, Gene expression patterns : GEP.

[10]  M. Farrar,et al.  Tonic BCR signaling represses receptor editing via Raf- and calcium-dependent signaling pathways. , 2011, Immunology letters.

[11]  M. Sakaguchi,et al.  Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues. , 2010, International journal of molecular medicine.

[12]  A. Hackam,et al.  Analysis of Dickkopf3 interactions with Wnt signaling receptors , 2010, Growth factors.

[13]  A. Waisman,et al.  Induction of B-cell development in adult mice reveals the ability of bone marrow to produce B-1a cells. , 2009, Blood.

[14]  C. Humpel,et al.  Dkk‐3 is elevated in CSF and plasma of Alzheimer’s disease patients , 2009, Journal of neurochemistry.

[15]  Wei Zhang,et al.  Dkk3, downregulated in cervical cancer, functions as a negative regulator of β‐catenin , 2009, International journal of cancer.

[16]  N. Ohkohchi,et al.  Differentially expressed genes in a porcine adult hepatic stem-like cell line and their expression in developing and regenerating liver , 2008, Laboratory Investigation.

[17]  T. Winkler,et al.  Siglec-G is a B1 cell–inhibitory receptor that controls expansion and calcium signaling of the B1 cell population , 2007, Nature Immunology.

[18]  L. Herzenberg,et al.  Division and differentiation of natural antibody-producing cells in mouse spleen , 2007, Proceedings of the National Academy of Sciences.

[19]  M. Hermann,et al.  Dickkopf-3 is expressed in a subset of adult human pancreatic beta cells , 2007, Histochemistry and Cell Biology.

[20]  E. Montecino-Rodriguez,et al.  Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential , 2007, Nature Reviews Immunology.

[21]  C. Niehrs,et al.  Function and biological roles of the Dickkopf family of Wnt modulators , 2006, Oncogene.

[22]  H. Fuchs,et al.  Generation and Characterization of dickkopf3 Mutant Mice , 2006, Molecular and Cellular Biology.

[23]  E. Montecino-Rodriguez,et al.  Identification of a B-1 B cell–specified progenitor , 2006, Nature Immunology.

[24]  K. Garrett,et al.  Constitutively active beta-catenin confers multilineage differentiation potential on lymphoid and myeloid progenitors. , 2005, Immunity.

[25]  I. Weissman,et al.  Frizzled 9 knock-out mice have abnormal B-cell development. , 2005, Blood.

[26]  L. Morel,et al.  Mechanisms of Peritoneal B-1a Cells Accumulation Induced by Murine Lupus Susceptibility Locus Sle21 , 2004, The Journal of Immunology.

[27]  J. Healey,et al.  Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. , 2004, Cancer research.

[28]  J. Kutok,et al.  B cell receptor signal strength determines B cell fate , 2004, Nature Immunology.

[29]  Georg C. Terstappen,et al.  Functional Characterization of WNT7A Signaling in PC12 Cells , 2003, Journal of Biological Chemistry.

[30]  J. Witztum,et al.  Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL , 2003, Nature Medicine.

[31]  N. Rose,et al.  Autoimmunity: busting the atherosclerotic plaque , 2003, Nature Medicine.

[32]  H. Wardemann,et al.  B-1a B Cells that Link the Innate and Adaptive Immune Responses Are Lacking in the Absence of the Spleen , 2002, The Journal of experimental medicine.

[33]  Marc Bonneville,et al.  Autoreactivity by design: innate B and T lymphocytes , 2001, Nature Reviews Immunology.

[34]  Jonathan C. Poe,et al.  A CD19-Dependent Signaling Pathway Regulates Autoimmunity in Lyn-Deficient Mice1 , 2001, The Journal of Immunology.

[35]  F. Kashanchi,et al.  Cell cycle effects of IL-10 on malignant B-1 cells , 2001, Genes and Immunity.

[36]  J. Kearney,et al.  Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. , 2001, Immunity.

[37]  Rainer Constien,et al.  Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line , 2001, Genesis.

[38]  T. Pawson,et al.  ICOS is essential for effective T-helper-cell responses , 2001, Nature.

[39]  J. Kearney,et al.  B‐cell subsets and the mature ­preimmune repertoire. Marginal zone and B1 B cells as part of a “natural immune memory” , 2000, Immunological reviews.

[40]  L. Herzenberg.  B‐1 cells: the lineage question revisited , 2000, Immunological reviews.

[41]  R. Zinkernagel,et al.  Control of early viral and bacterial distribution and disease by natural antibodies. , 1999, Science.

[42]  K. Robison,et al.  Functional and structural diversity of the human Dickkopf gene family. , 1999, Gene.

[43]  K. Rajewsky,et al.  B Cell Antigen Receptor Specificity and Surface Density Together Determine B-1 versus B-2 Cell Development , 1999, The Journal of experimental medicine.

[44]  L. Herzenberg,et al.  Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[45]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

[46]  G. Marti,et al.  Requirement for increased IL-10 in the development of B-1 lymphoproliferative disease in a murine model of CLL. , 1996, The Journal of clinical investigation.

[47]  T. Honjo,et al.  Administration of interleukin ‐5 or ‐10 activates peritoneal B‐1 cells and induces autoimmune hemolytic anemia in anti‐erythrocyte autoantibody‐transgenic mice , 1995, European journal of immunology.

[48]  Tasuku Honjo,et al.  B‐1 Cells and Autoimmunity a , 1995, Annals of the New York Academy of Sciences.

[49]  R. Grosschedl,et al.  Failure of B-cell differentiation in mice lacking the transcription factor EBF , 1995, Nature.

[50]  S. Clarke,et al.  Development of B-1 cells: segregation of phosphatidyl choline-specific B cells to the B-1 population occurs after immunoglobulin gene expression , 1994, The Journal of experimental medicine.

[51]  R. Hardy,et al.  Distinctive Developmental Origins and Specificities of Murine CD5+ B Cells , 1994, Immunological reviews.

[52]  R. Hardy,et al.  The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver , 1993, The Journal of experimental medicine.

[53]  J. García-Porrero,et al.  Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors , 1993, Nature.

[54]  R. Bucala.  Polyclonal activation of B lymphocytes by lipopolysaccharide requires macrophage-derived interleukin-1. , 1992, Immunology.

[55]  M. Howard,et al.  IL‐10 Production by CD5 B Cells , 1992, Annals of the New York Academy of Sciences.

[56]  L. Herzenberg,et al.  Adoptive Transfer of Murine B‐Cell Lineages , 1992, Annals of the New York Academy of Sciences.

[57]  M. Howard,et al.  Ly‐1 B (B‐1) cells are the main source of B cell‐derived interleukin 10 , 1992, European journal of immunology.

[58]  M. Apicella,et al.  The primary B cell response to the O/core region of bacterial lipopolysaccharide is restricted to the Ly-1 lineage. , 1991, Journal of immunology.

[59]  D. Isenberg,et al.  The relationship between CD5-expressing B lymphocytes and serologic abnormalities in rheumatoid arthritis patients and their relatives. , 1990, Arthritis and rheumatism.

[60]  N. Talal,et al.  B cells expressing CD5 are increased in Sjögren's syndrome. , 1988, Arthritis and rheumatism.

[61]  R. Barton,et al.  Ontogeny of terminal deoxynucleotidyl transferase-positive cells in lymphohemopoietic tissues of rat and mouse. , 1979, Journal of immunology.

[62]  N. Baumgarth.  The double life of a B-1 cell: self-reactivity selects for protective effector functions , 2011, Nature Reviews Immunology.

[63]  Jian Yu,et al.  Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer. , 2008, Carcinogenesis.

[64]  S. Pillai,et al.  Marginal zone B cells. , 2005, Annual review of immunology.

[65]  R. Berland,et al.  Origins and functions of B-1 cells with notes on the role of CD5. , 2002, Annual review of immunology.

[66]  R. Hardy,et al.  A VH11V kappa 9 B cell antigen receptor drives generation of CD5+ B cells both in vivo and in vitro. , 2000, Journal of immunology.

[67]  V. Kouskoff,et al.  B-cell-receptor-dependent positive and negative selection in immature B cells. , 2000, Current topics in microbiology and immunology.

[68]  R. Grosschedl,et al.  Control of lymphocyte differentiation by the LEF-1/TCF family of transcription factors. , 1999, Cold Spring Harbor symposia on quantitative biology.

[69]  A. Rolink,et al.  The surrogate light chain in mouse B-cell development. , 1996, International reviews of immunology.

[70]  C. Snapper,et al.  T cell-independent antigens type 2. , 1995, Annual review of immunology.

[71]  S. Bauer,et al.  The surrogate light chain in B-cell development. , 1993, Immunology today.

[72]  L. Herzenberg,et al.  Layered evolution in the immune system. A model for the ontogeny and development of multiple lymphocyte lineages. , 1992, Annals of the New York Academy of Sciences.