期刊
JOURNAL OF IMMUNOLOGY
卷 193, 期 1, 页码 268-276出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1203040
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资金
- Excellence Initiative of the German Federal Government
- Excellence Initiative of the German State Government [GSC-4, EXC294]
- Deutsche Forschungsgemeinschaft funds [SFB746]
Signal transduction from the BCR is regulated by the equilibrium between kinases (e. g., spleen tyrosine kinase [Syk]) and phosphatases (e.g., Shp-1). Previous studies showed that Syk-deficient B cells have a developmental block at the pro/pre-B cell stage, whereas a B cell-specific Shp-1 deficiency promoted B-1a cell development and led to autoimmunity. We generated B cell-specific Shp-1 and Syk double-knockout (DKO) mice and compared them to the single-knockout mice deficient for either Syk or Shp-1. Unlike Syk-deficient mice, the DKO mice can generate mature B cells, albeit at >20-fold reduced B cell numbers. The DKO B-2 cells are all Syk-negative, whereas the peritoneal B1 cells of the DKO mice still express Syk, indicating that they require this kinase for their proper development. The DKO B-2 cells cannot be stimulated via the BCR, whereas they are efficiently activated via TLR or CD40. We also found that in DKO pre-B cells, the kinase Zap70 is associated with the pre-BCR, suggesting that Zap70 is important to promote B cell maturation in the absence of Syk and SHP-1. Together, our data show that a properly balanced kinase/phosphatase equilibrium is crucial for normal B cell development and function.
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