Lee Keunwook, Gudapati Prathyusha, Dragovic Srdjan, Spencer Charles, Joyce Sebastian, Killeen Nigel, Magnuson Mark A, Boothby Mark
Department of Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Immunity. 2010 Jun 25;32(6):743-53. doi: 10.1016/j.immuni.2010.06.002.
Many functions of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) have been defined, but relatively little is known about the biology of an alternative mTOR complex, mTORC2. We showed that conditional deletion of rictor, an essential subunit of mTORC2, impaired differentiation into T helper 1 (Th1) and Th2 cells without diversion into FoxP3(+) status or substantial effect on Th17 cell differentiation. mTORC2 promoted phosphorylation of protein kinase B (PKB, or Akt) and PKC, Akt activity, and nuclear NF-kappaB transcription factors in response to T cell activation. Complementation with active Akt restored only T-bet transcription factor expression and Th1 cell differentiation, whereas activated PKC-theta reverted only GATA3 transcription factor and the Th2 cell defect of mTORC2 mutant cells. Collectively, the data uncover vital mTOR-PKC and mTOR-Akt connections in T cell differentiation and reveal distinct pathways by which mTORC2 regulates development of Th1 and Th2 cell subsets.
雷帕霉素哺乳动物靶蛋白（mTOR）复合物1（mTORC1）的许多功能已被明确，但对于另一种mTOR复合物mTORC2的生物学特性却知之甚少。我们发现，条件性敲除mTORC2的必需亚基rictor会损害向辅助性T细胞1（Th1）和Th2细胞的分化，而不会转向FoxP3（+）状态，对Th17细胞分化也没有实质性影响。mTORC2在T细胞活化时促进蛋白激酶B（PKB，即Akt）和蛋白激酶C（PKC）的磷酸化、Akt活性以及核内NF-κB转录因子的表达。用活性Akt进行补充仅恢复了T-bet转录因子的表达和Th1细胞的分化，而活化的PKC-θ仅逆转了GATA3转录因子以及mTORC2突变细胞的Th2细胞缺陷。总体而言，这些数据揭示了mTOR-PKC和mTOR-Akt在T细胞分化中的重要联系，并揭示了mTORC2调节Th1和Th2细胞亚群发育的不同途径。
