Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Immunol Rev. 2010 Sep;237(1):90-103. doi: 10.1111/j.1600-065X.2010.00942.x.
Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SW(HEL) model for analyzing antigen-specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation.
靶向修饰小鼠基因组提供了以精确和可控的方式操作复杂生理过程的能力。B 淋巴细胞生物学的研究不仅受益于靶向修饰控制 B 细胞存活和反应性的基因，还受益于通过靶向内源性免疫球蛋白基因座实现的抗原特异性操作。在这篇综述中，我们讨论了我们实验室使用基因靶向小鼠模型获得的最新结果，这些结果用于研究体内 B 细胞存活和反应性的调控。讨论了 TRAF2 和 TRAF3 信号蛋白对 BAFF 依赖性存活信号的控制，以及这些分子在 B 细胞谱系恶性肿瘤中的潜在作用。我们还概述了用于分析体内抗原特异性 B 细胞反应的 SW(HEL)模型的开发和使用。这包括对 T 依赖性 B 细胞分化过程中早期决策的控制、生发中心 B 细胞的亲和力成熟和浆细胞分化以及 EBI2 作为 B 细胞迁移和分化的关键调节剂的鉴定的深入了解。
