Analysis of Lyn/CD22 double-deficient B cells in vivo demonstrates Lyn- and CD22-independent pathways affecting BCR regulation and B cell survival
Analysis of Lyn/CD22 double-deficient B cells in vivo demonstrates Lyn- and CD22-independent pathways affecting BCR regulation and B cell survival
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DOI：
10.1002/eji.200535247
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发表时间：
2005-12-01
影响因子：
5.4
通讯作者：
Cornall, RJ
中科院分区：
文献类型：
--
作者：
Ferry, H;Cockford, TL;Cornall, RJ
B细胞命运由来自抗原受体和来自共受体的信号强度决定，所述共受体调节活化阈值并使B细胞适应其环境。这些共受体已被广泛地分为抑制和增强组，但有些，如CD 22，可能具有双重作用。CD 22募集多种信号增强剂，同时Lyn-dependent磷酸化导致抑制性磷酸酶SHP-1的结合。为了评估林恩和CD 22依赖性和非依赖性途径的相对重要性，我们产生了林恩和CD 22单缺陷小鼠和林恩/CD 22双缺陷小鼠，其表达针对鸡蛋溶菌酶的MD 4免疫球蛋白转基因（IG（HEL））。这种遗传学方法使我们能够比较林恩和CD 22对体内B细胞发育的贡献，独立于BCR特异性以及存在和不存在自身抗原。我们的研究结果表明，虽然林恩的影响是占主导地位的B细胞过度活跃的负调控，林恩和CD 22有独立的和累加的影响B细胞的生存。这些发现强调了BCR调控的微妙性质以及遗传互补对剖析共同和平行途径的有用性。
B cell fate is determined by the strength of signals from the antigen receptor and from co-receptors that adjust the activation threshold and tune the B cell to its environment. These co-receptors have been broadly classified into inhibitory and enhancing groups, yet some, such as CD22, may have dual effects. CD22 recruits a variety of signal enhancers at the same time as Lyn-dependent phosphorylation leads to the binding of the inhibitory phosphatase SHP-1. To assess the relative importance of Lyn- and CD22-dependent and -independent pathways, we generated Lyn and CD22 single-deficient mice and Lyn/CD22 double-deficient mice expressing the MD4 immunoglobulin transgene against hen egg lysozyme (Ig(HEL)). This genetic approach has enabled us to compare the contributions of Lyn and CD22 to B cell development in vivo, independent of BCR specificity and in the presence and absence of self-antigen. Our results show that although the effects of Lyn are dominant in negative regulation of B cell hyperactivity, Lyn and CD22 have independent and additive effects on B cell survival. These findings emphasize the subtle nature of regulation at the BCR and the usefulness of genetic complementation to dissect common and parallel pathways.