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 sig-naling 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. B cells are subdivided into B1 and B2 cells. The names were chosen due to the observation that B1 cells develop earlier than B2 cells during ontogeny (1, 2). B1 and B2 cells are found in different anatomical locations, have different surface markers, and fulfill their functions in different types of immune responses (3). B2 cells are generally responsible for the adaptive Ab response, whereas B1 cells serve as a first line of defense as part of the innate immune system, by secreting most of natural IgM (4, 5). B1 cells are commonly subdivided into B1a and B1b B cells according to the expression of CD5, which is expressed on B1a cells, but not on B1b cells. Both B1 cell subsets are present at a high proportion of 30–70% of the total B cells, depending on the mouse strain, in the pleural and peritoneal cavity (3). B2 cells are subdivided into follicular (FO) and marginal zone (MZ) B cells. FO B cells present the majority of B cells in the body, with .95% of B cells in lymph nodes (LN) and .70% of B cells in the spleen (3). MZ B cells are only found in the MZ of the spleen and have a distinct function in comparison with FO B cells. Similar to B1 …