Cytokine Biology Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):E1849-56. doi: 10.1073/pnas.1305070110. Epub 2013 Apr 29.
Screening a complete mouse phosphatase lentiviral shRNA library using high-throughput sequencing revealed several phosphatases that regulate CD4 T-cell differentiation. We concentrated on two lipid phosphatases, the myotubularin-related protein (MTMR)9 and -7. Silencing MTMR9 by shRNA or siRNA resulted in enhanced T-helper (Th)1 differentiation and increased Th1 protein kinase B (PKB)/AKT phosphorylation while silencing MTMR7 caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells. Irradiated mice reconstituted with MTMR9 shRNA-transduced bone marrow cells had an elevated proportion of T-box transcription factor T-bet expressors among their CD4 T cells. After adoptive transfer of naïve cells from such reconstituted mice, immunization resulted in a greater proportion of T-box transcription factor T-bet-expressing cells. Thus, myotubularin-related proteins have a role in controlling in vitro and in vivo Th-cell differentiation, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity.
利用高通量测序筛选完整的小鼠磷酸酶慢病毒 shRNA 文库，揭示了几种调节 CD4 T 细胞分化的磷酸酶。我们集中研究了两种脂质磷酸酶，肌管素相关蛋白（MTMR）9 和 -7。shRNA 或 siRNA 沉默 MTMR9 导致 T 辅助（Th）1 分化增强，Th1 蛋白激酶 B（PKB）/AKT 磷酸化增加，而沉默 MTMR7 导致 Th2 和 Th17 分化增加，这些细胞中的 AKT 磷酸化增加。用 MTMR9 shRNA 转导的骨髓细胞重建的辐照小鼠，其 CD4 T 细胞中 T 盒转录因子 T-bet 表达者的比例升高。从这种重建的小鼠中过继转移幼稚细胞后，免疫接种导致 T 盒转录因子 T-bet 表达细胞的比例增加。因此，肌管素相关蛋白在控制体外和体内 Th 细胞分化中具有作用，可能通过调节磷脂酰肌醇[3,4,5]-三磷酸活性。
