Btk regulates multiple stages in the development and survival of B-1 cells

Abstract

B-1 cells are important players in the first line of defense against pathogens. According to current models for the origin of B-1 cells, they either represent a separate lineage from conventional B-2 cells or differentiate from conventional B-2 cells via an intermediate, B-1(int), in response to positive selection by antigen. Here we show that Btk, a Tec family kinase that mediates B cell antigen receptor (BCR) signaling, is required at multiple stages of B-1 cell development. VH12 anti-phosphatidylcholine (PtC) IgH transgenic mice provide a model for the induced differentiation of B-1 cells. This transgene selects for PtC-reactive cells and induces them to adopt a B-1 phenotype. Both processes have been shown to depend on Btk. To determine whether this is secondary to a requirement for Btk in the development of mature B-2 cells, we crossed VH12 transgenic mice to mice expressing low levels of Btk. B-2 cell development occurs normally in Btk(lo) mice despite reduced responsiveness to BCR crosslinking. Analysis of VH12.Btk(lo) mice reveals that Btk regulates the B-1(int) to B-1 transition and/or the survival of splenic B-1 cells, in part via a mechanism independent of its role in BCR signaling. We also show that Btk mediates the survival of, and expression of IL-10 by, those B-1 cells that do develop and migrate to the peritoneum. Multiple roles for Btk in B-1 cell development and maintenance may explain the particular sensitivity of this population to mutations in components of Btk signaling pathways.

Tyrosine Kinase Btk Is Required for NK Cell Activation

“…Btk has been shown to be crucial for B cell development, differentiation and function because of its predominant expression in different developmental stages of B lymphocytes, from hematopoietic stem cells, common lymphoid progenitor, to pre-B, pro-B, immature, and mature B cells (4). For example, Btk deficiency is associated with lack of circulating mature B cells and low reactivity to TI antigens of B cells, revealing a profound block in central B cell development and responsiveness of B cells (5,6). Moreover, individuals with mutation of the gene encoding Btk, diagnosed as X-linked agammaglobulinemia (XLA), suffer from the disabled generation of all classes of immunoglobulins and therefore fail to mount effective humoral immune responses (7).…”

The ARID Family Transcription Factor Bright Is Required for both Hematopoietic Stem Cell and B Lineage Development

“…Btk is required for both B-1 generation and normal PC responses (11) and acts principally at the checkpoints (pre-B1 and T1) most compromised in both Bright KO and DN mice (13). These defects were previously observed, albeit less dramatically, in Bright DN transgenic mice (39).…”

Transgenic Mice Expressing Dominant-Negative Bright Exhibit Defects in B1 B Cells

“…In support of that hypothesis, IgM secretion was impaired in DN Bright peritoneal B cells, and production of the secretory form of IgM was repressed relative to controls. Btk may also contribute to Bright function in B1 cells as indicated by experiments with mice expressing intermediate levels of Btk and suggesting that Btk plays a role in B1 cell maintenance once they develop (41). Because DN Bright may not have been expressed in the earliest B1 B cell progenitors, we cannot assess whether Bright is also important for B1 lineage development.…”