Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution
Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution
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DOI：
10.1093/intimm/dxp049
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发表时间：
2009-07-01
影响因子：
4.4
通讯作者：
Satterthwaite, Anne B.
中科院分区：
文献类型：
--
作者：
Hinman, Rochelle M.;Nichols, Whitney A.;Satterthwaite, Anne B.
B细胞抗原受体（BCR）交联促进成熟B细胞的增殖和存活。磷酸肌醇-3-激酶介导的促凋亡和抗有丝分裂基因如Foxo家族转录因子的下调是该过程的重要组成部分。以前，我们证明了BCR信号降低了Foxo 1，Foxo 3和Foxo 4的转录本表达。我们现在表明，BCR诱导的Foxo 3和Foxo 4 mRNA表达下调通过与Foxo 1不同的机制发生。虽然Foxo 1、Foxo 3和Foxo 4结合相同的DNA序列，但它们在B细胞活化后表达的差异控制表明它们在B谱系中可能具有独特的功能。为了开始解决这个问题，我们评估了Foxo 3-/-小鼠中的B细胞发育和功能。在脾B细胞区室中未观察到Foxo 3缺乏对以下参数的影响：亚群分布、增殖、体外分化和Foxo靶基因细胞周期蛋白G2和B细胞易位基因1的表达。然而，Foxo 3-/-小鼠表现出IgG 2a、IgG 3和伊加的基础水平增加。在Foxo 3-/-骨髓中也观察到前B细胞数量显著减少。最后，在Foxo 3-/-小鼠中，骨髓和外周血中的再循环B细胞减少，这可能是由于介导淋巴器官排出的1-磷酸鞘氨醇受体的表达低于正常水平。因此，Foxo 3对B细胞发育、B细胞定位和IG水平的控制做出独特贡献。
B cell antigen receptor (BCR) cross-linking promotes proliferation and survival of mature B cells. Phosphoinositide-3-kinase-mediated down-regulation of pro-apoptotic and anti-mitogenic genes such as the Foxo family of transcription factors is an important component of this process. Previously, we demonstrated that BCR signaling decreases expression of transcripts for Foxo1, Foxo3 and Foxo4. We now show that BCR-Induced down-regulation of Foxo3 and Foxo4 mRNA expression occurs via distinct mechanisms from those established for Foxo1. While Foxo1, Foxo3 and Foxo4 bind the same DNA sequence, the differential control of their expression upon B cell activation suggests that they may have unique functions in the B lineage. To begin to address this issue, we evaluated B cell development and function in Foxo3-/- mice. No effect of Foxo3 deficiency was observed with respect to the following parameters in the splenic B cell compartment: sub-population distribution, proliferation, in vitro differentiation and expression of the Foxo target genes cyclin G2 and B cell translocation gene 1. However, Foxo3-/- mice demonstrated increased basal levels of IgG2a, IgG3 and IgA. A significant reduction in pre-B cell numbers was also observed in Foxo3-/- bone marrow. Finally, recirculating B cells in the bone marrow and peripheral blood were decreased in Foxo3-/- mice, perhaps due to lower than normal expression of receptor for sphingosine-1 phosphate, which mediates egress from lymphoid organs. Thus, Foxo3 makes a unique contribution to B cell development, B cell localization and control of Ig levels.