Mechanism of B cell proliferation and diffentiation in peripheral lymphoid organs

B细胞在外周淋巴器官的发育需要与滤泡树突状细胞（FDC）密切相互作用。FDC提供抗原、趋化因子和细胞因子，支持B细胞生长和分化。然后，包括NF-kappaB在内的转录机制被激活。本研究主要通过基因靶向方法在体内阐明这些步骤。FDC产生一种趋化因子BLC，已知BLC在体外作用于成熟的B细胞。为了明确其在体内的作用，我们建立了blc缺陷小鼠。缺乏blc的小鼠出生时健康。我们计划分析B细胞在外周淋巴器官的分布、FDC分化和blc缺陷小鼠的免疫反应。IKK激酶(IKK) α和β都能激活NF-kappaB活性，这对B细胞的生长和分化至关重要。虽然这两种激酶表现出相似的分子结构和功能，但不同组织对它们的需求是不同的。ikkalpha缺陷小鼠出生后很快死亡，因为肢体和表皮畸形。为了分析IKKalpha如何在B细胞中发挥关键作用，我们通过将IKKalpha缺陷的胎肝细胞转移到辐照小鼠中，建立了IKKalpha缺陷嵌合小鼠。ikkalpha缺陷嵌合体成熟B细胞数量的减少主要通过增强细胞凋亡来实现。他们还表现出免疫球蛋白产生和免疫反应的严重损害。结果表明ikkβ在外周血淋巴器官B细胞的生长和分化中是必需的，单独ikkβ不能正常激活成熟B细胞中的NF-kappaB。我们已经建立了缺乏转录因子C/EBPgamma的突变小鼠。C/ ebpγ缺乏的自然杀伤（NK）细胞显示NK活性和干扰素γ产生的损害。新的基因被认为参与了C/ ebγ介导的NK活性。C/EBPgamma靶基因的鉴定目前正在进行中。

B cell development in peripheral lymphoid organs requires an intimate interaction with follicular dendritic cells (FDC). FDC provides antigens, chemokines, and cyokines, which support B cell growth and differentiation. Then, transcriptional machinery including NF-kappaB is activated. This study aims to clarify these steps in vivo mainly by using gene targeting approach.1. FDC produces a chemokine, BLC, which is known to act on mature B cells in vitro. In order to clarify its in vivo roles, we have established BLC-deficient mice. BLC-deficient mice were born healthy. We plan to analyze B cell distribution in peripheral lymphoid organs, FDC differentiation, and immune responses in BLC-deficient mice.2. Both IkappaB kinase (IKK) alpha and beta activate NF-kappaB activities, which are critical for B cell growth and differentiation. Although these two kinases shows similar molecular structures and functions, they are differentially required for various tissues. IKKalpha-deficient mice die soon after birth because of limb and epidermis malformation. In order to analyze how IKKalpha plays critical roles in B cells, we have established IKKalpha-deficient chimeric mice by transferring IKKalpha-deficient fetal liver cells into irradiated mice. IKKalpha-deficient chimeras showed decrease of mature B cell population mainly through enhanced apoptosis. They also showed severe impairment of immunoglobulin production and immune response. The results suggest that IKKalpha is essential for B cell growth and differentiation in peripheral lymphoid organs and that IKKbeta alone cannot properly activate NF-kappaB in mature B cells.3. We have established the mutant mice lacking a transcription factor, C/EBPgamma. C/EBPgamma-deficient natural killer (NK) cells showed impairment of NK activity and interferon-gamma production. Novel gene(s) were assumed to be involved in C/EBPgamma-mediated NK activity. Identification of the target gene of C/EBPgamma is now in progress.