Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany; and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany.
Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany.
J Immunol. 2014 Jul 1;193(1):268-76. doi: 10.4049/jimmunol.1203040. Epub 2014 Jun 4.
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.
BCR 信号转导受激酶（如脾酪氨酸激酶[Syk]）和磷酸酶（如 Shp-1）之间的平衡调节。先前的研究表明，Syk 缺陷的 B 细胞在原 B 细胞/前 B 细胞阶段存在发育阻滞，而 B 细胞特异性 Shp-1 缺陷则促进了 B1a 细胞的发育，并导致自身免疫。我们生成了 B 细胞特异性 Shp-1 和 Syk 双敲除（DKO）小鼠，并将其与缺失 Syk 或 Shp-1 的单敲除小鼠进行了比较。与 Syk 缺陷型小鼠不同，DKO 小鼠可以产生成熟的 B 细胞，尽管 B 细胞数量减少了 20 多倍。DKO B-2 细胞均为 Syk 阴性，而 DKO 小鼠的腹腔 B1 细胞仍表达 Syk，表明它们需要这种激酶才能正常发育。DKO B-2 细胞不能通过 BCR 被激活，而通过 TLR 或 CD40 可以有效地被激活。我们还发现，在 DKO 前 B 细胞中，激酶 Zap70 与前 BCR 相关，表明在缺乏 Syk 和 SHP-1 的情况下，Zap70 对促进 B 细胞成熟很重要。综上所述，我们的数据表明，适当的激酶/磷酸酶平衡对于正常的 B 细胞发育和功能至关重要。
