Integrated Department of Immunology, National Jewish Health and University of Colorado Denver, Denver, CO 80206, USA.
J Exp Med. 2010 Mar 15;207(3):607-21. doi: 10.1084/jem.20091673. Epub 2010 Feb 22.
B cell receptors (BCRs) generate tonic signals critical for B cell survival and early B cell development. To determine whether these signals also mediate the development of transitional and mature B cells, we examined B cell development using a mouse strain in which nonautoreactive immunoglobulin heavy and light chain-targeted B cells express low surface BCR levels. We found that reduced BCR expression translated into diminished tonic BCR signals that strongly impaired the development of transitional and mature B cells. Constitutive expression of Bcl-2 did not rescue the differentiation of BCR-low B cells, suggesting that this defect was not related to decreased cell survival. In contrast, activation of the Ras pathway rescued the differentiation of BCR-low immature B cells both in vitro and in vivo, whereas extracellular signal-regulated kinase (Erk) inhibition impaired the differentiation of normal immature B cells. These results strongly suggest that tonic BCR signaling mediates the differentiation of immature into transitional and mature B cells via activation of Erk, likely through a pathway requiring Ras.
B 细胞受体 (BCR) 产生的持续信号对于 B 细胞的存活和早期发育至关重要。为了确定这些信号是否也介导了过渡性和成熟 B 细胞的发育，我们使用一种小鼠品系来检查 B 细胞的发育，在这种小鼠中，非自身反应性免疫球蛋白重链和轻链靶向的 B 细胞表达低表面 BCR 水平。我们发现 BCR 表达的减少转化为持续 BCR 信号的减弱，强烈损害了过渡性和成熟 B 细胞的发育。BCR-低 B 细胞的组成性 Bcl-2 表达不能挽救其分化，这表明这种缺陷与细胞存活减少无关。相比之下，Ras 通路的激活在体外和体内均挽救了 BCR-低不成熟 B 细胞的分化，而细胞外信号调节激酶 (Erk) 抑制则损害了正常不成熟 B 细胞的分化。这些结果强烈表明，持续的 BCR 信号通过激活 Erk 介导了未成熟 B 细胞向过渡性和成熟 B 细胞的分化，可能通过需要 Ras 的途径。
