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Rafi Ahmed - One of the best experts on this subject based on the ideXlab platform.
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AbsTracT B142: Long non-coding RNA expression during CD8+ T Cell differenTiaTion and exhausTion
Other Topics, 2016Co-Authors: William H. Hudson, Haydn T. Kissick, Masao Hashimoto, Rafi AhmedAbstract:ExhausTion of CD8 + T lymphocyTes is a major barrier To effecTive clearance of chronic viral infecTion and cancer by The immune sysTem. TranscripTional changes underlie The expansion and differenTiaTion of a naive CD8 + T Cell inTo various effecTor subseTs, including The exhausTed sTaTe. ExperimenTs from oTher Cell Types have shown ThaT The majoriTy of The mammalian genome is Transcribed, generaTing a large number of long, non-proTein-coding RNAs (lncRNAs). These lncRNAs have been shown To play imporTanT roles in many Cellular processes including hisTone modificaTion, TranscripTional regulaTion, and mRNA meTabolism. To idenTify The role of lncRNAs in CD8 + T Cell differenTiaTion and exhausTion, we performed RNA-sequencing on funcTional and exhausTed CD8 + T Cells in boTh humans and mice. We idenTified over 1,000 expressed, previously un-annoTaTed lncRNAs; of These, hundreds are differenTially expressed over The course of CD8+ T Cell differenTiaTion. ExhausTed CD8 + T Cells express a unique seT of lncRNAs, and This profile is alTered wiTh IL-2 TreaTmenT. These resulTs suggesT ThaT lncRNAs play imporTanT roles in T Cell differenTiaTion and exhausTion, and furTher sTudy is underway To deTermine Their funcTional roles in anTi-viral and anTi-Tumor immune responses. CiTaTion FormaT: William Hudson, Haydn Kissick, Masao HashimoTo, Rafi Ahmed. Long non-coding RNA expression during CD8 + T Cell differenTiaTion and exhausTion [absTracT]. In: Proceedings of The Second CRI-CIMT-EATI-AACR InTernaTional Cancer ImmunoTherapy Conference: TranslaTing Science inTo Survival; 2016 SepT 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):AbsTracT nr B142.
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TranslaTional conTrol of memory CD8 T Cell differenTiaTion (LYM4P.752)
Journal of Immunology, 2014Co-Authors: Koichi Araki, Bogumila T. Konieczny, Masahiro Morita, Nahum Sonenberg, Rafi AhmedAbstract:CD8 T Cells play an essenTial role in conTrolling viral as well as inTraCellular bacTerial and parasiTic infecTions. Memory CD8 T Cells provide proTecTive immuniTy upon re-encounTer wiTh The same paThogens. A beTTer undersTanding of memory CD8 T Cell developmenT is criTical for The raTional design of vaccines. TranscripTome analyses in anTigen-specific CD8 T Cells have made a significanT conTribuTion To characTerize global re-programming of gene expression during memory CD8 T Cell differenTiaTion. However, There has been minimal emphasis on undersTanding TranslaTional conTrol of gene expression in anTigen specific CD8 T Cells. To examine mRNA TranslaTion during memory CD8 T Cell differenTiaTion, we performed longiTudinal analyses of polysome profiles in anTigen-specific CD8 T Cells afTer acuTe LCMV infecTion. We found ThaT mRNA TranslaTion was dynamically regulaTed during CD8 T Cell responses; TranslaTion acTiviTy was significanTly enhanced during clonal expansion phase, and iT immediaTely reTurned To basal level aT The peak of CD8 T Cell responses. Genome-wide analyses of mRNA TranslaTion showed ThaT a significanT number of mRNAs were TranslaTionally regulaTed during CD8 T Cell responses. FurTher experimenTs revealed ThaT TranslaTional conTrol of gene expression plays an imporTanT role in memory CD8 T Cell formaTion. Thus, our sTudies provide a framework for undersTanding TranslaTional regulaTion ThaT occurs during memory T Cell differenTiaTion.
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The role of mTOR in memory CD8 T-Cell differenTiaTion.
Immunological reviews, 2010Co-Authors: Koichi Araki, Benjamin Youngblood, Rafi AhmedAbstract:The mammalian TargeT of rapamycin (mTOR) is an inTraCellular kinase ThaT regulaTes Cell growTh and meTabolism. ITs specific inhibiTor rapamycin is currenTly used in TransplanT recipienTs as an immunosuppressive drug To prevenT allografT rejecTion. STudies have shown complex and diverse mechanisms for The immunosuppressive effecTs of rapamycin. The drug has been reporTed To inhibiT T-Cell proliferaTion, induce anergy, modulaTe T-Cell Trafficking, promoTe regulaTory T Cells, and also prevenT maTuraTion of dendriTic Cells as well as producTion of Type I inTerferon. However, several oTher sTudies have paradoxically demonsTraTed immunosTimulaTory effecTs of rapamycin by improving anTigen presenTaTion and regulaTing cyTokine producTion from macrophages and myeloid dendriTic Cells. RecenTly, iT has been shown ThaT rapamycin also exhibiTs immunosTimulaTory effecTs on memory CD8(+) T-Cell differenTiaTion. The drug improved boTh quanTiTy and qualiTy of memory CD8(+) T Cells induced by viral infecTion and vaccinaTion, showing ThaT mTOR is a major regulaTor of memory CD8(+) T-Cell differenTiaTion. These discoveries have implicaTions for The developmenT of novel vaccine regimens. Here, we review The role of mTOR in memory CD8(+) T-Cell differenTiaTion and compare The effecT of rapamycin among CD8(+) T Cells, CD4(+) T Cells, and dendriTic Cells. Also, we discuss poTenTial applicaTion of These findings in a clinical seTTing.
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mTor regulaTes memory cd8 T Cell differenTiaTion
Nature, 2009Co-Authors: Koichi Araki, Alexandra P. Turner, Susanne A. Keller, Virginia Oliva Shaffer, Shivaprakash Gangappa, Christian P. Larsen, Martin F. Bachmann, Rafi AhmedAbstract:mTOR, parT of The PI3K–AKT–mTOR Cell-signalling cascade and a TargeT for The anTiTumour drug rapamycin, is idenTified here as a regulaTor of CD8 T-Cell differenTiaTion. DespiTe iTs primarily immunosuppressive acTiviTy, rapamycin can enhance immune responses To experimenTal vaccines in mice and monkeys. This counTerinTuiTive finding poinTs To The abiliTy To increase The funcTional qualiTies of memory T Cells as a poTenTial way of enhancing The efficacy of vaccines againsT paThogens and cancers. Inducing effecTive memory T-Cell responses is a major goal of vaccines againsT chronic infecTions and Tumours. Here, mTOR, The mammalian TargeT for The immunosuppressive drug rapamycin, is shown To enhance The quanTiTy and qualiTy of virus-specific CD8 T Cells in mouse and non-human primaTe models. Memory CD8 T Cells are a criTical componenT of proTecTive immuniTy, and inducing effecTive memory T-Cell responses is a major goal of vaccines againsT chronic infecTions and Tumours1,2,3. Considerable efforT has gone inTo designing vaccine regimens ThaT will increase The magniTude of The memory response, buT There has been minimal emphasis on developing sTraTegies To improve The funcTional qualiTies of memory T Cells4. Here we show ThaT mTOR (mammalian TargeT of rapamycin5, also known as FRAP1) is a major regulaTor of memory CD8 T-Cell differenTiaTion, and in conTrasT To whaT we expecTed, The immunosuppressive drug rapamycin has immunosTimulaTory effecTs on The generaTion of memory CD8 T Cells. TreaTmenT of mice wiTh rapamycin following acuTe lymphocyTic choriomeningiTis virus infecTion enhanced noT only The quanTiTy buT also The qualiTy of virus-specific CD8 T Cells. Similar effecTs were seen afTer immunizaTion of mice wiTh a vaccine based on non-replicaTing virus-like parTicles. In addiTion, rapamycin TreaTmenT also enhanced memory T-Cell responses in non-human primaTes following vaccinaTion wiTh modified vaccinia virus Ankara. Rapamycin was effecTive during boTh The expansion and conTracTion phases of The T-Cell response; during The expansion phase iT increased The number of memory precursors, and during The conTracTion phase (effecTor To memory TransiTion) iT acceleraTed The memory T-Cell differenTiaTion program. ExperimenTs using RNA inTerference To inhibiT expression of mTOR, rapTor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in anTigen-specific CD8 T Cells showed ThaT mTOR acTs inTrinsically Through The mTORC1 (mTOR complex 1) paThway To regulaTe memory T-Cell differenTiaTion. Thus These sTudies idenTify a molecular paThway regulaTing memory formaTion and provide an effecTive sTraTegy for improving The funcTional qualiTies of vaccine- or infecTion-induced memory T Cells.
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mTOR regulaTes memory CD8 T-Cell differenTiaTion
Nature, 2009Co-Authors: Koichi Araki, Alexandra P. Turner, Susanne A. Keller, Virginia Oliva Shaffer, Shivaprakash Gangappa, Christian P. Larsen, Martin F. Bachmann, Rafi AhmedAbstract:Memory CD8 T Cells are a criTical componenT of proTecTive immuniTy, and inducing effecTive memory T-Cell responses is a major goal of vaccines againsT chronic infecTions and Tumours. Considerable efforT has gone inTo designing vaccine regimens ThaT will increase The magniTude of The memory response, buT There has been minimal emphasis on developing sTraTegies To improve The funcTional qualiTies of memory T Cells. Here we show ThaT mTOR (mammalian TargeT of rapamycin, also known as FRAP1) is a major regulaTor of memory CD8 T-Cell differenTiaTion, and in conTrasT To whaT we expecTed, The immunosuppressive drug rapamycin has immunosTimulaTory effecTs on The generaTion of memory CD8 T Cells. TreaTmenT of mice wiTh rapamycin following acuTe lymphocyTic choriomeningiTis virus infecTion enhanced noT only The quanTiTy buT also The qualiTy of virus-specific CD8 T Cells. Similar effecTs were seen afTer immunizaTion of mice wiTh a vaccine based on non-replicaTing virus-like parTicles. In addiTion, rapamycin TreaTmenT also enhanced memory T-Cell responses in non-human primaTes following vaccinaTion wiTh modified vaccinia virus Ankara. Rapamycin was effecTive during boTh The expansion and conTracTion phases of The T-Cell response; during The expansion phase iT increased The number of memory precursors, and during The conTracTion phase (effecTor To memory TransiTion) iT acceleraTed The memory T-Cell differenTiaTion program. ExperimenTs using RNA inTerference To inhibiT expression of mTOR, rapTor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in anTigen-specific CD8 T Cells showed ThaT mTOR acTs inTrinsically Through The mTORC1 (mTOR complex 1) paThway To regulaTe memory T-Cell differenTiaTion. Thus These sTudies idenTify a molecular paThway regulaTing memory formaTion and provide an effecTive sTraTegy for improving The funcTional qualiTies of vaccine- or infecTion-induced memory T Cells.
Koichi Araki - One of the best experts on this subject based on the ideXlab platform.
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TranslaTional conTrol of memory CD8 T Cell differenTiaTion (LYM4P.752)
Journal of Immunology, 2014Co-Authors: Koichi Araki, Bogumila T. Konieczny, Masahiro Morita, Nahum Sonenberg, Rafi AhmedAbstract:CD8 T Cells play an essenTial role in conTrolling viral as well as inTraCellular bacTerial and parasiTic infecTions. Memory CD8 T Cells provide proTecTive immuniTy upon re-encounTer wiTh The same paThogens. A beTTer undersTanding of memory CD8 T Cell developmenT is criTical for The raTional design of vaccines. TranscripTome analyses in anTigen-specific CD8 T Cells have made a significanT conTribuTion To characTerize global re-programming of gene expression during memory CD8 T Cell differenTiaTion. However, There has been minimal emphasis on undersTanding TranslaTional conTrol of gene expression in anTigen specific CD8 T Cells. To examine mRNA TranslaTion during memory CD8 T Cell differenTiaTion, we performed longiTudinal analyses of polysome profiles in anTigen-specific CD8 T Cells afTer acuTe LCMV infecTion. We found ThaT mRNA TranslaTion was dynamically regulaTed during CD8 T Cell responses; TranslaTion acTiviTy was significanTly enhanced during clonal expansion phase, and iT immediaTely reTurned To basal level aT The peak of CD8 T Cell responses. Genome-wide analyses of mRNA TranslaTion showed ThaT a significanT number of mRNAs were TranslaTionally regulaTed during CD8 T Cell responses. FurTher experimenTs revealed ThaT TranslaTional conTrol of gene expression plays an imporTanT role in memory CD8 T Cell formaTion. Thus, our sTudies provide a framework for undersTanding TranslaTional regulaTion ThaT occurs during memory T Cell differenTiaTion.
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The role of mTOR in memory CD8 T-Cell differenTiaTion.
Immunological reviews, 2010Co-Authors: Koichi Araki, Benjamin Youngblood, Rafi AhmedAbstract:The mammalian TargeT of rapamycin (mTOR) is an inTraCellular kinase ThaT regulaTes Cell growTh and meTabolism. ITs specific inhibiTor rapamycin is currenTly used in TransplanT recipienTs as an immunosuppressive drug To prevenT allografT rejecTion. STudies have shown complex and diverse mechanisms for The immunosuppressive effecTs of rapamycin. The drug has been reporTed To inhibiT T-Cell proliferaTion, induce anergy, modulaTe T-Cell Trafficking, promoTe regulaTory T Cells, and also prevenT maTuraTion of dendriTic Cells as well as producTion of Type I inTerferon. However, several oTher sTudies have paradoxically demonsTraTed immunosTimulaTory effecTs of rapamycin by improving anTigen presenTaTion and regulaTing cyTokine producTion from macrophages and myeloid dendriTic Cells. RecenTly, iT has been shown ThaT rapamycin also exhibiTs immunosTimulaTory effecTs on memory CD8(+) T-Cell differenTiaTion. The drug improved boTh quanTiTy and qualiTy of memory CD8(+) T Cells induced by viral infecTion and vaccinaTion, showing ThaT mTOR is a major regulaTor of memory CD8(+) T-Cell differenTiaTion. These discoveries have implicaTions for The developmenT of novel vaccine regimens. Here, we review The role of mTOR in memory CD8(+) T-Cell differenTiaTion and compare The effecT of rapamycin among CD8(+) T Cells, CD4(+) T Cells, and dendriTic Cells. Also, we discuss poTenTial applicaTion of These findings in a clinical seTTing.
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mTor regulaTes memory cd8 T Cell differenTiaTion
Nature, 2009Co-Authors: Koichi Araki, Alexandra P. Turner, Susanne A. Keller, Virginia Oliva Shaffer, Shivaprakash Gangappa, Christian P. Larsen, Martin F. Bachmann, Rafi AhmedAbstract:mTOR, parT of The PI3K–AKT–mTOR Cell-signalling cascade and a TargeT for The anTiTumour drug rapamycin, is idenTified here as a regulaTor of CD8 T-Cell differenTiaTion. DespiTe iTs primarily immunosuppressive acTiviTy, rapamycin can enhance immune responses To experimenTal vaccines in mice and monkeys. This counTerinTuiTive finding poinTs To The abiliTy To increase The funcTional qualiTies of memory T Cells as a poTenTial way of enhancing The efficacy of vaccines againsT paThogens and cancers. Inducing effecTive memory T-Cell responses is a major goal of vaccines againsT chronic infecTions and Tumours. Here, mTOR, The mammalian TargeT for The immunosuppressive drug rapamycin, is shown To enhance The quanTiTy and qualiTy of virus-specific CD8 T Cells in mouse and non-human primaTe models. Memory CD8 T Cells are a criTical componenT of proTecTive immuniTy, and inducing effecTive memory T-Cell responses is a major goal of vaccines againsT chronic infecTions and Tumours1,2,3. Considerable efforT has gone inTo designing vaccine regimens ThaT will increase The magniTude of The memory response, buT There has been minimal emphasis on developing sTraTegies To improve The funcTional qualiTies of memory T Cells4. Here we show ThaT mTOR (mammalian TargeT of rapamycin5, also known as FRAP1) is a major regulaTor of memory CD8 T-Cell differenTiaTion, and in conTrasT To whaT we expecTed, The immunosuppressive drug rapamycin has immunosTimulaTory effecTs on The generaTion of memory CD8 T Cells. TreaTmenT of mice wiTh rapamycin following acuTe lymphocyTic choriomeningiTis virus infecTion enhanced noT only The quanTiTy buT also The qualiTy of virus-specific CD8 T Cells. Similar effecTs were seen afTer immunizaTion of mice wiTh a vaccine based on non-replicaTing virus-like parTicles. In addiTion, rapamycin TreaTmenT also enhanced memory T-Cell responses in non-human primaTes following vaccinaTion wiTh modified vaccinia virus Ankara. Rapamycin was effecTive during boTh The expansion and conTracTion phases of The T-Cell response; during The expansion phase iT increased The number of memory precursors, and during The conTracTion phase (effecTor To memory TransiTion) iT acceleraTed The memory T-Cell differenTiaTion program. ExperimenTs using RNA inTerference To inhibiT expression of mTOR, rapTor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in anTigen-specific CD8 T Cells showed ThaT mTOR acTs inTrinsically Through The mTORC1 (mTOR complex 1) paThway To regulaTe memory T-Cell differenTiaTion. Thus These sTudies idenTify a molecular paThway regulaTing memory formaTion and provide an effecTive sTraTegy for improving The funcTional qualiTies of vaccine- or infecTion-induced memory T Cells.
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mTOR regulaTes memory CD8 T-Cell differenTiaTion
Nature, 2009Co-Authors: Koichi Araki, Alexandra P. Turner, Susanne A. Keller, Virginia Oliva Shaffer, Shivaprakash Gangappa, Christian P. Larsen, Martin F. Bachmann, Rafi AhmedAbstract:Memory CD8 T Cells are a criTical componenT of proTecTive immuniTy, and inducing effecTive memory T-Cell responses is a major goal of vaccines againsT chronic infecTions and Tumours. Considerable efforT has gone inTo designing vaccine regimens ThaT will increase The magniTude of The memory response, buT There has been minimal emphasis on developing sTraTegies To improve The funcTional qualiTies of memory T Cells. Here we show ThaT mTOR (mammalian TargeT of rapamycin, also known as FRAP1) is a major regulaTor of memory CD8 T-Cell differenTiaTion, and in conTrasT To whaT we expecTed, The immunosuppressive drug rapamycin has immunosTimulaTory effecTs on The generaTion of memory CD8 T Cells. TreaTmenT of mice wiTh rapamycin following acuTe lymphocyTic choriomeningiTis virus infecTion enhanced noT only The quanTiTy buT also The qualiTy of virus-specific CD8 T Cells. Similar effecTs were seen afTer immunizaTion of mice wiTh a vaccine based on non-replicaTing virus-like parTicles. In addiTion, rapamycin TreaTmenT also enhanced memory T-Cell responses in non-human primaTes following vaccinaTion wiTh modified vaccinia virus Ankara. Rapamycin was effecTive during boTh The expansion and conTracTion phases of The T-Cell response; during The expansion phase iT increased The number of memory precursors, and during The conTracTion phase (effecTor To memory TransiTion) iT acceleraTed The memory T-Cell differenTiaTion program. ExperimenTs using RNA inTerference To inhibiT expression of mTOR, rapTor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in anTigen-specific CD8 T Cells showed ThaT mTOR acTs inTrinsically Through The mTORC1 (mTOR complex 1) paThway To regulaTe memory T-Cell differenTiaTion. Thus These sTudies idenTify a molecular paThway regulaTing memory formaTion and provide an effecTive sTraTegy for improving The funcTional qualiTies of vaccine- or infecTion-induced memory T Cells.
Axel Kallies - One of the best experts on this subject based on the ideXlab platform.
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id2 mediaTed inhibiTion of e2a represses memory cd8 T Cell differenTiaTion
Journal of Immunology, 2013Co-Authors: Frederick Masson, Martina Minnich, Moshe Olshansky, Ivan Bilic, Adele M Mount, Axel Kallies, Terence P Speed, Meinrad BusslingerAbstract:The TranscripTion facTor inhibiTor of DNA binding (Id)2 modulaTes T Cell faTe decisions, buT The molecular mechanism underpinning This regulaTion is unclear. In This sTudy we show ThaT loss of Id2 cripples effecTor differenTiaTion and insTead programs CD8+ T Cells To adopT a memory faTe wiTh increased Eomesodermin and Tcf7 expression. We demonsTraTe ThaT Id2 resTrains CD8+ T Cell memory differenTiaTion by inhibiTing E2A-mediaTed direcT acTivaTion of Tcf7 and ThaT Id2 expression level mirrors T Cell memory recall capaciTy. As a resulT of The defecTive effecTor differenTiaTion, Id2-deficienT CD8+ T Cells fail To induce sufficienT Tbx21 expression To generaTe shorT-lived effecTor CD8+ T Cells. Our findings reveal ThaT The Id2/E2A axis orchesTraTes T Cell differenTiaTion Through The inducTion or repression of downsTream TranscripTion facTors essenTial for effecTor and memory T Cell differenTiaTion.
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DisTincT regulaTion of effecTor and memory T-Cell differenTiaTion.
Immunology and cell biology, 2008Co-Authors: Axel KalliesAbstract:Three major subseTs of anTigen-experienced T Cells have been idenTified based on surface markers and disTincT funcTional properTies: shorT-lived effecTor T Cells, cenTral memory T Cells and effecTor memory T Cells. The precise relaTionship among These subseTs and Their mode of differenTiaTion are sTill conTroversial. RecenT sTudies, however, have provided compelling evidence for an early delineaTion of The effecTor versus memory T-Cell faTes regulaTed Through specific TranscripTion facTors. CyTokines have long been recognized as being imporTanT for The shaping of a T-Cell response and for The mainTenance of memory T Cells. The observaTion ThaT shorT-lived effecTor and memory T Cells, as well as Their precursors, express disTincT levels of IL7R has provided an imporTanT Tool To examine The role ThaT cyTokines play in The programming of T-Cell differenTiaTion paThways and of The TranscripTional regulaTors ThaT guide These processes. IL2 and IL12 in parTicular have been shown To provide The signals ThaT induce or repress TranscripTion facTors, such as T-beT, Eomes and Blimp-1, all of which are crucial in The differenTiaTion and homoeosTasis of effecTor and memory T Cells. The coordinaTed differenTiaTion of a heTerogeneous populaTion of anTigen-specific T Cells early during an immune response is essenTial for The effecTive eradicaTion of paThogens and The long-Term proTecTion againsT reinfecTion. Thus, undersTanding The signals and TranscripTional programmes in T-Cell differenTiaTion is a key To successful manipulaTion of T-Cell responses during vaccinaTion.
Futoshi Nara - One of the best experts on this subject based on the ideXlab platform.
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DichloroaceTaTe induces regulaTory T-Cell differenTiaTion and suppresses Th17-Cell differenTiaTion by pyruvaTe dehydrogenase kinase-independenT mechanism.
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Naoyuki Makita, Jun Ishiguro, Keisuke Suzuki, Futoshi NaraAbstract:ObjecTives RecenTly, There has been a growing inTeresT in The mechanism of acTion of dichloroaceTaTe (DCA) for T-Cell differenTiaTion; however, This mechanism has noT been elucidaTed in deTail. Therefore, This sTudy aimed To invesTigaTe The mechanism of acTion of DCA for Treg and Th17 differenTiaTion wiTh pyruvaTe dehydrogenase kinase (PDHK) inhibiTor (AZD7545) and PDHK knockdown. MeThods InhibiTory acTiviTy of DCA and AZD7545 againsT recombinanT PDHK and inTraCellular PDH phosphorylaTion was measured. The effecTs of DCA and AZD7545 on T-Cell differenTiaTion were assessed by analysing Foxp3+ T-Cell populaTions for Treg differenTiaTion and IL-17A producTion for Th17 differenTiaTion. For reacTive oxygen species (ROS) producTion, DCFDA was used as an indicaTor. Key findings DichloroaceTaTe and AZD7545 inhibiTed PDHK acTiviTy of recombinanT PDHK and inTraCellular PDH phosphorylaTion. DCA was capable of inducing Treg differenTiaTion and suppressing Th17 differenTiaTion. The effecTs of DCA were independenT of PDHK because neiTher AZD7545 nor knockdown of PDHK1 or PDHK3 affecTed T-Cell differenTiaTion. DCA was deTermined To be capable of inducing ROS producTion, and The effecTs of DCA on T-Cell differenTiaTion were shown To be dependenT on ROS producTion. Conclusions DichloroaceTaTe possesses Treg inducTion and Th17 suppression, which is independenT of PDHK and dependenT on ROS producTion.
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DichloroaceTaTe induces regulaTory T‐Cell differenTiaTion and suppresses Th17‐Cell differenTiaTion by pyruvaTe dehydrogenase kinase‐independenT mechanism
The Journal of pharmacy and pharmacology, 2016Co-Authors: Naoyuki Makita, Jun Ishiguro, Keisuke Suzuki, Futoshi NaraAbstract:ObjecTives RecenTly, There has been a growing inTeresT in The mechanism of acTion of dichloroaceTaTe (DCA) for T-Cell differenTiaTion; however, This mechanism has noT been elucidaTed in deTail. Therefore, This sTudy aimed To invesTigaTe The mechanism of acTion of DCA for Treg and Th17 differenTiaTion wiTh pyruvaTe dehydrogenase kinase (PDHK) inhibiTor (AZD7545) and PDHK knockdown. MeThods InhibiTory acTiviTy of DCA and AZD7545 againsT recombinanT PDHK and inTraCellular PDH phosphorylaTion was measured. The effecTs of DCA and AZD7545 on T-Cell differenTiaTion were assessed by analysing Foxp3+ T-Cell populaTions for Treg differenTiaTion and IL-17A producTion for Th17 differenTiaTion. For reacTive oxygen species (ROS) producTion, DCFDA was used as an indicaTor. Key findings DichloroaceTaTe and AZD7545 inhibiTed PDHK acTiviTy of recombinanT PDHK and inTraCellular PDH phosphorylaTion. DCA was capable of inducing Treg differenTiaTion and suppressing Th17 differenTiaTion. The effecTs of DCA were independenT of PDHK because neiTher AZD7545 nor knockdown of PDHK1 or PDHK3 affecTed T-Cell differenTiaTion. DCA was deTermined To be capable of inducing ROS producTion, and The effecTs of DCA on T-Cell differenTiaTion were shown To be dependenT on ROS producTion. Conclusions DichloroaceTaTe possesses Treg inducTion and Th17 suppression, which is independenT of PDHK and dependenT on ROS producTion.
Fengyang Lei - One of the best experts on this subject based on the ideXlab platform.
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C‐Myc‐induced survivin is essenTial for promoTing The NoTch-dependenT T Cell differenTiaTion from hemaTopoieTic sTem Cells
Genes, 2017Co-Authors: Rizwanul Haque, Fengyang Lei, Jianyong Song, Mohammad Nazmul Haque, Praneet Sandhu, Song Guo Zheng, Deyu Fang, Jin-ming Yang, Jianxun SongAbstract:NoTch is indispensable for T Cell lineage commiTmenT, and is needed for ThymocyTe differenTiaTion aT early phases. During early sTages of T Cell developmenT, acTive NoTch prevenTs oTher lineage poTenTials including B Cell lineage and myeloid Cell (e.g., dendriTic Cell) lineage. NeverTheless, The precise inTraCellular signaling paThways by which NoTch promoTes T Cell differenTiaTion remain unclear. Here we reporT ThaT The TranscripTion facTor c-Myc is a key mediaTor of The NoTch signaling-regulaTed T Cell differenTiaTion. In a well-esTablished in viTro differenTiaTion model of T lymphocyTes from hemaTopoieTic sTem Cells, we showed ThaT NoTch1 and 4 direcTly promoTed c-Myc expression; dominanT-negaTive (DN) c-Myc inhibiTed early T Cell differenTiaTion. Moreover, The c-Myc expression acTivaTed by NoTch signaling increased The expression of survivin, an inhibiTor of apopTosis (IAP) proTein. We furTher demonsTraTed ThaT over-expression of c-Myc increased The abundance of survivin and The T Cell differenTiaTion Thereof, whereas dn c-Myc reduced survivin levels and concomiTanTly reTarded The differenTiaTion. The c-Myc-dependenT survivin inducTion is funcTionally germane, because NoTch-dependenT T Cell differenTiaTion was canceled by The depleTion of survivin. These resulTs idenTify boTh c-Myc and survivin as imporTanT mediaTors of The NoTch signaling-regulaTed differenTiaTion of T lymphocyTes from hemaTopoieTic sTem Cells.
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C-Myc regulaTion by NoTch Signaling ModulaTes T Cell DifferenTiaTion
Journal of Immunology, 2016Co-Authors: Jim Song, Rizwanul Haque, Xinmeng Song, Fengyang LeiAbstract:NoTch signaling is essenTial for T lineage commiTmenT and furTher required during early phases of ThymocyTe differenTiaTion. AcTive NoTch signaling during early sTages of T Cell developmenT inhibiTs oTher lineage poTenTials, such as B Cell and myeloid Cell ( e.g. , dendriTic Cell) poTenTials. However, The inTraCellular signaling paThways by which NoTch signaling regulaTes T Cell differenTiaTion remain unknown. Here we show ThaT The TranscripTional facTor c-Myc is conTrolled by NoTch signaling which regulaTes T Cell differenTiaTion. In a well-esTablished in viTro differenTiaTion of T lymphocyTes from sTem Cells, NoTch signaling direcTly conTrols c-Myc expression. Overexpression of acTive c-Myc promoTes while dominanT-negaTive (dn) c-Myc inhibiTs early Cell differenTiaTion. Moreover, c-Myc expression mediaTed by NoTch signaling modulaTes survivin, an inhibiTor of apopTosis (IAP) proTein, which is crucial for T Cell developmenT. Overexpression of acTive c-Myc increases while dn c-Myc reduces survivin expression, which corresponds To T Cell differenTiaTion wiThin The in viTro differenTiaTion sysTem. These resulTs idenTify c-Myc, TogeTher wiTh survivin, as regulaTors of The differenTiaTion of T Cells from NoTch signaling.
