Emerging studies highlight the import-ance of metabolic reprogramming in T cell development and function, although how these processes are regulated remains to be fully understood. Recent advances in dissecting the ro...Emerging studies highlight the import-ance of metabolic reprogramming in T cell development and function, although how these processes are regulated remains to be fully understood. Recent advances in dissecting the roles of Sinl-m T0RC2 signaling in early thymocyte development provide new in sight into the dynamic in terplay between immune signaling and cell metabolism, as well as the crucial role in directi ng thymocyte pro life ration and development.展开更多
目的:探讨一氧化氮(NO)对肠上皮细胞表达紧密连接蛋白Occludin的影响,以研究NO对肠黏膜屏障的作用机制.方法:将NO的供体Sin1与肠上皮细胞株Caco-2共培养24 h,采用MTT方法观察NO对肠上皮细胞的作用,并分别提取细胞蛋白和总RNA,采用免疫...目的:探讨一氧化氮(NO)对肠上皮细胞表达紧密连接蛋白Occludin的影响,以研究NO对肠黏膜屏障的作用机制.方法:将NO的供体Sin1与肠上皮细胞株Caco-2共培养24 h,采用MTT方法观察NO对肠上皮细胞的作用,并分别提取细胞蛋白和总RNA,采用免疫蛋白印迹(Westem blot)蛋白半定量方法和实时定量聚合酶链式反应(RO-PCR)方法检测不同NO浓度对Caco-2细胞表达紧密连接蛋白Occludin蛋白和mRNA表达的影响.结果:随着Sin1浓度升高(125,250,500和1000μmol/L)NO对细胞的杀伤作用产生并逐渐增大,Occludin蛋白表达量和mRNA的相对表达量与无Sin1刺激时蛋白及mRNA的表达量相比明显降低(蛋白:375±0.5,374±0.8,363±0.3.363±0.7 vs 398±0.7;mRNA:0.689±0.01,0.578±0.09,0.554±0.03,0.619±0.04 vs 1,均P<0.01).结论:NO可直接损伤肠上皮细胞,同时以剂量依赖形式在蛋白和分子水平影响紧密连接蛋白Occludin的表达.展开更多
CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encou...CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial infection.Simultaneously,a fraction of these cells become long-lived memory CD8^(+)T cells that combat future infections.Notably,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute vs.chronic immunization)or fluctuations in host metabolic,inflammatory,or aging factors.Therefore,many T cells may be lost or become exhausted and no longer functional.Complicated intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this process.Therefore,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular immunity.In this review,we focus on mammalian target of rapamycin(mTOR),particularly signaling mediated by mTOR complex(mTORC)2 in memory and exhausted CD8^(+)T cells at the molecular level.展开更多
Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell develo...Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell development,homeostasis and immune responses.However,our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete.Recent studies have begun to shed light on this important pathway.We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a.We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin(Ig)gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism.Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells.Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells.We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.展开更多
文摘Emerging studies highlight the import-ance of metabolic reprogramming in T cell development and function, although how these processes are regulated remains to be fully understood. Recent advances in dissecting the roles of Sinl-m T0RC2 signaling in early thymocyte development provide new in sight into the dynamic in terplay between immune signaling and cell metabolism, as well as the crucial role in directi ng thymocyte pro life ration and development.
文摘目的:探讨一氧化氮(NO)对肠上皮细胞表达紧密连接蛋白Occludin的影响,以研究NO对肠黏膜屏障的作用机制.方法:将NO的供体Sin1与肠上皮细胞株Caco-2共培养24 h,采用MTT方法观察NO对肠上皮细胞的作用,并分别提取细胞蛋白和总RNA,采用免疫蛋白印迹(Westem blot)蛋白半定量方法和实时定量聚合酶链式反应(RO-PCR)方法检测不同NO浓度对Caco-2细胞表达紧密连接蛋白Occludin蛋白和mRNA表达的影响.结果:随着Sin1浓度升高(125,250,500和1000μmol/L)NO对细胞的杀伤作用产生并逐渐增大,Occludin蛋白表达量和mRNA的相对表达量与无Sin1刺激时蛋白及mRNA的表达量相比明显降低(蛋白:375±0.5,374±0.8,363±0.3.363±0.7 vs 398±0.7;mRNA:0.689±0.01,0.578±0.09,0.554±0.03,0.619±0.04 vs 1,均P<0.01).结论:NO可直接损伤肠上皮细胞,同时以剂量依赖形式在蛋白和分子水平影响紧密连接蛋白Occludin的表达.
基金This work was supported by grants from the National Natural Science Foundation of China(31930035,91942311,and 32061143028 to BS,32200738 to YC32170895 to NW)+5 种基金National Key R&D Program of China(2021YFA1301400 to BS)Shanghai Science and Technology Commission(20410714000,20JC410100,and 22JC1402600 to BS,22ZR1480700,22QA1408000 to NW)Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases to BS,China Postdoctoral Science Foundation(2022T150422 to YC,2021M692127 to HS)Nurture projects for basic research of Shanghai Chest Hospital(2021YNJCQ6 to XO).HS and YC are YuHe Postdoctoral Fellow at Shanghai Institute of ImmunologyYC is also supported by fellowships from Shanghai Postdoctoral Excellence Program(2021250)and China International Postdoctoral Exchange Fellowship Program(Talent-Introduction Program)ZX is supported by the Zhi-Yuan Endowed fund from Shanghai Jiao Tong University.
文摘CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial infection.Simultaneously,a fraction of these cells become long-lived memory CD8^(+)T cells that combat future infections.Notably,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute vs.chronic immunization)or fluctuations in host metabolic,inflammatory,or aging factors.Therefore,many T cells may be lost or become exhausted and no longer functional.Complicated intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this process.Therefore,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular immunity.In this review,we focus on mammalian target of rapamycin(mTOR),particularly signaling mediated by mTOR complex(mTORC)2 in memory and exhausted CD8^(+)T cells at the molecular level.
基金supported in part by grant AI 063348(NIH)and PR093728(DOD)(to B.S.).
文摘Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell development,homeostasis and immune responses.However,our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete.Recent studies have begun to shed light on this important pathway.We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a.We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin(Ig)gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism.Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells.Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells.We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.
