The catalytic PI3K isoforms p110γ and p110δ contribute to B cell development and maintenance, transformation, and proliferation
The catalytic PI3K isoforms p110γ and p110δ contribute to B cell development and maintenance, transformation, and proliferation
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DOI：
10.1189/jlb.0809585
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发表时间：
2010-06-01
影响因子：
5.5
通讯作者：
Piekorz, Roland P.
中科院分区：
文献类型：
--
作者：
Beer-Hammer, Sandra;Zebedin, Eva;Piekorz, Roland P.
I类PI 3 K依赖性信号传导调节细胞增殖、分化和存活。对基因缺陷小鼠的分析揭示了造血表达的PI 3 K催化亚基p110 γ和p110 δ在T和B淋巴细胞的发育和功能中的特定作用。然而，在B细胞谱系中这两种PI 3 K亚型之间的功能冗余仍然不清楚。在这里，我们表明，p110 δ和p110 γ表达在B细胞在早期发育阶段。正常的B细胞分化需要两种亚型，因为与单一缺陷相比，p110 γ/p110 δ双重缺陷导致CD 43（hi）/B220（+）/CD 19（-）细胞百分比增加。有趣的是，与单缺陷细胞相比，双缺陷细胞在p185 bcr-abl或v-abl癌基因转化后B细胞前体的初始转化效率显著降低。p110 γ/p110 δ双缺陷小鼠和用双缺陷BM重建的致死性辐照野生型小鼠的脾B细胞数量减少强调了B细胞发育中对p110 γ和p110 δ的需求。此外，p110 γ/p110 δ双缺陷T和B细胞的外周维持在将双缺陷脾细胞过继转移到野生型小鼠中后高度受损。在功能上，LPS刺激脾细胞显示增殖缺陷，导致p110 γ/p110 δ双缺陷B细胞存活率降低，这与D型细胞周期蛋白和Bcl-X-L诱导受损相关。令人惊讶的是，当分析纯化的B细胞时没有观察到这一点，表明可能的细胞外源性因子对双缺陷B细胞的增殖受损有贡献。因此，我们提供了新的证据表明，p110 γ和p110 δ有重叠和细胞外的作用，在发展，外周血维持和功能的B细胞。J. Leukoc. 87：1083-1095; 2010.
Class I PI3K-dependent signaling regulates cell proliferation, differentiation, and survival. Analysis of gene-deficient mice revealed specific roles for the hematopoietically expressed PI3K catalytic subunits, p110 gamma and p110 delta, in development and function of T and B lymphocytes. However, the functional redundancy between these two PI3K isoforms in the B cell lineage remains unclear. Here, we demonstrate that p110 delta and p110 gamma are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110 gamma/p110 delta double deficiency causes an increased percentage of CD43(hi)/B220(+)/CD19(-) cells as compared with single deficiency. Interestingly, initial transformation efficiency of B cell precursors was strongly reduced in double-deficient cells following transformation by p185 bcr-abl or v-abl oncogenes as compared with single-deficient cells. The requirement of p110 gamma and p110 delta in B cell development is underlined by reduced splenic B cell numbers of p110 gamma/p110 delta double-deficient mice and of lethally irradiated wild-type mice reconstituted with double-deficient BM. Moreover, the peripheral maintenance of p110 gamma/p110 delta double-deficient T and B cells was highly impaired following adoptive transfer of double-deficient splenocytes into wildtype mice. Functionally, LPS stimulation of splenocytes revealed proliferation defects resulting in decreased survival of p110 gamma/p110 delta double-deficient B cells, which correlated with impaired induction of D-type cyclins and Bcl-X-L. Surprisingly, this was not observed when purified B cells were analyzed, indicating a contribution of likely cell-extrinsic factor(s) to the impaired proliferation of double-deficient B cells. Thus, we provide novel evidence that p110 gamma and p110 delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells. J. Leukoc. Biol. 87: 1083-1095; 2010.