Donahue Amber C, Hess Kristen L, Ng Kwan L, Fruman David A
Center for Immunology and Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
Int Immunol. 2004 Dec;16(12):1789-98. doi: 10.1093/intimm/dxh180. Epub 2004 Nov 1.
The signaling enzyme phosphoinositide 3-kinase (PI3K) is activated following B cell receptor (BCR) engagement and by many other receptors on B lymphocytes. Mice lacking p85alpha, the predominant PI3K regulatory isoform, exhibit defects in B cell development and activation that are grossly similar to those found in mice lacking Bruton's tyrosine kinase (Btk) and other critical signaling molecules. However, a detailed analysis of splenic B cell subsets in p85alpha-deficient mice has not been reported. Here we show that these mice are deficient in four major B cell subsets: transitional-1, transitional-2, follicular and marginal zone. These defects are distinct from those observed in Xid mice that express a mutant Btk unable to interact with PI3K lipid products. Moreover, mice with both genetic lesions exhibit even greater impairment in B cell development. Finally, we show that transgenic expression of the anti-apoptotic protein Bcl-2 in p85alpha-deficient mice restores the transitional B cell subsets but not the marginal zone subset, and produces a follicular population with an aberrant phenotype. These findings establish a role for PI3K-p85alpha in differentiation of both follicular and marginal zone B cells, and suggest that these functions are required not solely for the propagation of anti-apoptotic signals.
信号酶磷脂酰肌醇3激酶（PI3K）在B细胞受体（BCR）结合后以及B淋巴细胞上的许多其他受体作用下被激活。缺乏p85α（PI3K主要的调节亚型）的小鼠在B细胞发育和激活方面存在缺陷，这些缺陷与缺乏布鲁顿酪氨酸激酶（Btk）和其他关键信号分子的小鼠中发现的缺陷极为相似。然而，尚未有关于p85α缺陷小鼠脾脏B细胞亚群的详细分析报道。在此我们表明，这些小鼠在四个主要B细胞亚群中存在缺陷：过渡1型、过渡2型、滤泡型和边缘区B细胞。这些缺陷与在表达无法与PI3K脂质产物相互作用的突变型Btk的Xid小鼠中观察到的缺陷不同。此外，同时具有这两种基因损伤的小鼠在B细胞发育方面表现出更严重的损伤。最后，我们表明在p85α缺陷小鼠中抗凋亡蛋白Bcl-2的转基因表达恢复了过渡性B细胞亚群，但未恢复边缘区亚群，并产生了具有异常表型的滤泡型群体。这些发现确立了PI3K-p85α在滤泡型和边缘区B细胞分化中的作用，并表明这些功能不仅是抗凋亡信号传导所必需的。
