1. Abteilung für Pharmakologie und Experimentelle Therapie, Klinikum der Eberhard-Karls-Universität Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
J Leukoc Biol. 2010 Jun;87(6):1083-95. doi: 10.1189/jlb.0809585. Epub 2010 Mar 3.
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, p110gamma and p110delta, 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 p110delta and p110gamma are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110gamma/p110delta 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 p110gamma and p110delta in B cell development is underlined by reduced splenic B cell numbers of p110gamma/p110delta double-deficient mice and of lethally irradiated wild-type mice reconstituted with double-deficient BM. Moreover, the peripheral maintenance of p110gamma/p110delta double-deficient T and B cells was highly impaired following adoptive transfer of double-deficient splenocytes into wild-type mice. Functionally, LPS stimulation of splenocytes revealed proliferation defects resulting in decreased survival of p110gamma/p110delta 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 p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
I 类 PI3K 依赖性信号调节细胞增殖、分化和存活。对基因缺陷小鼠的分析表明，造血表达的 PI3K 催化亚基 p110γ和 p110δ在 T 和 B 淋巴细胞的发育和功能中具有特定作用。然而，这两种 PI3K 同工酶在 B 细胞谱系中的功能冗余尚不清楚。在这里，我们证明 p110δ和 p110γ在早期发育阶段在 B 细胞中表达。正常 B 细胞分化需要这两种同工酶，因为 p110γ/p110δ 双缺失导致 CD43(hi)/B220(+)/CD19(-)细胞的比例增加，与单缺失相比。有趣的是，与单缺陷细胞相比，p185 bcr-abl 或 v-abl 癌基因转化后的 B 细胞前体的初始转化效率在双缺陷细胞中大大降低。p110γ和 p110δ在 B 细胞发育中的作用是由 p110γ/p110δ 双缺失小鼠脾脏 B 细胞数量减少和致死性辐照野生型小鼠用双缺失 BM 重建所强调的。此外，在将双缺失的脾细胞过继转移到野生型小鼠中后，p110γ/p110δ 双缺失 T 和 B 细胞的外周维持受到严重损害。功能上，LPS 刺激脾细胞显示出增殖缺陷，导致 p110γ/p110δ 双缺失 B 细胞的存活率降低，这与 D 型细胞周期蛋白和 Bcl-X(L)的诱导受损相关。令人惊讶的是，当分析纯化的 B 细胞时没有观察到这种情况，表明可能存在细胞外在因素（s）对双缺失 B 细胞增殖的损害。因此，我们提供了新的证据，表明 p110γ 和 p110δ 在 B 细胞的发育、外周维持和功能中具有重叠和细胞外在的作用。
