The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells

摘要

B cell antigen receptor signals development. activation, prolifera- tion, or apoptosis of B cells depending on their condition, and its proper signaling is critical for activation and homeostasis of the immune system. The B cell-restricted adaptor protein BASH (also termed BLNK/SLP-65) is rapidly phosphorylated by the tyrosine kinase Syk after BCR ligation and binds to various signaling proteins. BASH structurally resembles SLP-76, which is essential for T cell development and T cell receptor signaling. To evaluate the role for BASH in B cell development and function in vivo. we disrupted BASH alleles in embryonic stem cells by means of homologous recombination and used these cells to complement lymphocyte-incompetent blastocysts from RAG2-deficient mice. In the resultant chimeric mice, T cell development was apparently normal. but B cell development was impaired, and a normally rare population of large preB cells expressing preB cell receptor dom- inated in the bone marrow in place of small preB cells, although they were mostly noncycling. In addition, the mature B cell pop- ulations in the periphery and the bone marrow profoundly de- creased in size, as did B-1 cells in the peritoneal cavity. and serum Ig was severely reduced. The BASH-deficient B cells scarcely pro- Iiferated or up-regulated B7-2 in response to BCR ligation and poorly proliferated upon CD40 ligation or lipopolysaccharide stim- ulation. This phenotype indicates that BASH is critical for preB cell receptor signaling inducing proliferation of large preB cells and the following differentiation, for peripheral B cell maturation, and for BCR signaling inducing activation/proliferation of B cells.