Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling
Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling
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DOI：
10.1016/j.immuni.2006.08.015
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发表时间：
2006-10-01
期刊：
影响因子：
32.4
通讯作者：
Rickert, Robert C.
中科院分区：
文献类型：
--
作者：
Omori, Sidne A.;Cato, Matthew H.;Rickert, Robert C.
类别转换重组（CSR）是体液免疫的关键。然而，对CSR的监管并没有完全理解。在这里，我们证明，磷脂酰肌醇3-激酶（PI 3 K）积极抑制的发病和频率的CSR在原代B细胞。一致地，在B细胞中缺乏脂质磷酸酶PTEN的小鼠由于受损的CSR而表现出高IgM状况，其可以通过特异性抑制PI 3 K δ在体外恢复。PI 3 K对CSR的抑制作用部分依赖于转录因子BLIMP 1，BLIMP 1将浆细胞定型和CSR停止联系起来。丝氨酸-苏氨酸激酶Akt的PI 3 K依赖性活化部分通过转录因子的叉头盒家族（Foxo）的失活来抑制CSR。PI 3 K信号的减少增强了AID（激活诱导的胞苷脱氨酶）的表达并加速了CSR。然而，AID的异位表达不能完全克服PI 3 K对CSR的抑制，表明PI 3 K调节AID的表达和功能。
Class-switch recombination (CSR) is essential for humoral immunity. However, the regulation of CSR is not completely understood. Here we demonstrate that phosphaticlylinositol 3-kinase (PI3K) actively suppressed the onset and frequency of CSR in primary B cells. Consistently, mice lacking the lipid phosphatase, PTEN, in B cells exhibited a hyper-IgM condition due to impaired CSR, which could be restored in vitro by specific inhibition of PI3K delta. Inhibition of CSR by PI3K was partially dependent on the transcription factor, BLIMP1, linking plasma cell commitment and cessation of CSR. PI3K-dependent activation of the serine-threonine kinase, Akt, suppressed CSR, in part, through the inactivation of the Forkhead Box family (Foxo)of transcription factors. Reduced PI3K signaling enhanced the expression of AID (activation-induced cytidine deaminase) and accelerated CSR. However, ectopic expression of AID could not fully overcome inhibition of CSR by PI3K, suggesting that PI3K regulates both the expression and function of AID.