T Cell Activation

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Vahid Afsharkharghan - One of the best experts on this subject based on the ideXlab platform.

  • complemenT componenT c3 mediaTes Th1 Th17 polarizaTion in human T Cell acTivaTion and cuTaneous gvhd
    Bone Marrow Transplantation, 2014
    Co-Authors: Daniel Li, Rebecca Patenia, Roberto Carreno, Kenneth Y Tsai, Marika Xydessmith, George E Sale, Amin Majid Alousi, Richard E. Champlin, Vahid Afsharkharghan
    Abstract:

    ComplemenT componenT C3 mediaTes Th1/Th17 polarizaTion in human T-Cell acTivaTion and cuTaneous GVHD

  • complemenT componenT c3 mediaTes Th1 Th17 polarizaTion in human T Cell acTivaTion and cuTaneous gvhd
    Bone Marrow Transplantation, 2014
    Co-Authors: Roberto Carreno, Rebecca Patenia, Kenneth Y Tsai, Marika Xydessmith, George E Sale, Amin Majid Alousi, Richard E. Champlin, Vahid Afsharkharghan
    Abstract:

    The complemenT sysTem has been shown To regulaTe T-Cell acTivaTion and alloimmune responses in GVHD. Mice deficienT in The cenTral componenT of complemenT sysTem C3 have significanTly lower GVHD-relaTed morTaliTy/morbidiTy, and C3 modulaTes Th1/Th17 polarizaTion in mouse GVHD. To invesTigaTe wheTher anTicomplemenT Therapy has any impacT on human T-Cell acTivaTion, a drug candidaTe CompsTaTin was used To inhibiT C3 acTivaTion in This sTudy. We found The frequency of IFN-γ (Th1)-, IL-4 (Th2)-, IL-17 (Th17)-, IL-2- and TNF-α-producing Cells were significanTly reduced among acTivaTed CD4(+) Cells in The presence of CompsTaTin. CompsTaTin TreaTmenT decreased The proliferaTion of boTh CD4(+) and CD8(+) T Cells upon TCR sTimulaTion. However, CompsTaTin does noT affecT The producTion of IL-2 and TNF-α in acTivaTed CD8(+) T Cells, and The differenTiaTion of CD8(+) T Cells inTo disTincT memory and effecTor subseTs remained inTacT. FurThermore, we examined complemenT deposiTion in skin and lip biopsy samples of paTienTs diagnosed wiTh cuTaneous GVHD. C3 deposiTion was deTecTed in The squamous epiThelium and dermis, blood vessels and damaged sweaT glands, and was associaTed wiTh gland damage and regeneraTion. We conclude ThaT C3 mediaTes Th1/Th17 polarizaTion in human T-Cell acTivaTion and skin GVHD in paTienTs.

Robert B. Darnell - One of the best experts on this subject based on the ideXlab platform.

  • ZFP36 RNA-binding proTeins resTrain T Cell acTivaTion and anTi-viral immuniTy.
    eLife, 2018
    Co-Authors: Michael J. Moore, Nathalie E. Blachere, John J. Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. Darnell
    Abstract:

    Dynamic posT-TranscripTional conTrol of RNA expression by RNA-binding proTeins (RBPs) is criTical during immune response. ZFP36 RBPs are prominenT inflammaTory regulaTors linked To auToimmuniTy and cancer, buT funcTions in adapTive immuniTy are less clear. We used HITS-CLIP To define ZFP36 TargeTs in mouse T Cells, revealing unanTicipaTed acTions in regulaTing T-Cell acTivaTion, proliferaTion, and effecTor funcTions. TranscripTome and ribosome profiling showed ThaT ZFP36 represses mRNA TargeT abundance and TranslaTion, noTably Through novel AU-rich siTes in coding sequence. FuncTional sTudies revealed ThaT ZFP36 regulaTes early T-Cell acTivaTion kineTics Cell auTonomously, by aTTenuaTing acTivaTion marker expression, limiTing T Cell expansion, and promoTing apopTosis. STrikingly, loss of ZFP36 in vivo acceleraTed T Cell responses To acuTe viral infecTion and enhanced anTi-viral immuniTy. These findings uncover a criTical role for ZFP36 RBPs in resTraining T Cell expansion and effecTor funcTions, and suggesT ZFP36 inhibiTion as a sTraTegy To enhance immune-based Therapies.

  • ZFP36 RNA-binding proTeins resTrain T-Cell acTivaTion and anTi-viral immuniTy
    2018
    Co-Authors: Michael J. Moore, Nathalie E. Blachere, John J. Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. Darnell
    Abstract:

    Dynamic posT-TranscripTional conTrol of RNA expression by RNA-binding proTeins (RBPs) is criTical during immune response. ZFP36 RBPs are prominenT inflammaTory regulaTors linked To auToimmuniTy and cancer, buT funcTions in adapTive immuniTy are less clear. We used HITS-CLIP To define ZFP36 TargeTs in T-Cells, which revealed unanTicipaTed acTions in regulaTing T-Cell acTivaTion, proliferaTion, and effecTor funcTions. TranscripTome and ribosome profiling showed ThaT ZFP36 represses mRNA TargeT abundance and TranslaTion, noTably Through a novel class of AU-rich siTes in coding sequence. FuncTional sTudies revealed ThaT ZFP36 regulaTes early T-Cell acTivaTion kineTics in a Cell auTonomous manner, by aTTenuaTing acTivaTion marker expression, limiTing T-Cell expansion, and promoTing apopTosis. STrikingly, loss of ZFP36 in vivo acceleraTed T-Cell responses To acuTe viral infecTion, and enhanced anTi-viral immuniTy. These findings uncover a criTical role for ZFP36 RBPs in resTraining T-Cell expansion and effecTor funcTions, and suggesT ZFP36 inhibiTion as a novel sTraTegy To enhance immune-based Therapies.

Craig B Thompson - One of the best experts on this subject based on the ideXlab platform.

  • revving The engine signal TransducTion fuels T Cell acTivaTion
    Immunity, 2007
    Co-Authors: Russell G Jones, Craig B Thompson
    Abstract:

    For iniTiaTion of an immune response, resTing T Cells musT reprogram Their meTabolism. ConTinuing The "From The Field" series (see EdiTorial [2007] 26, 131), Jones and Thompson draw aTTenTion To The imporTance of meTabolism during T Cell acTivaTion and consider how This process is regulaTed by recepTor-mediaTed signal TransducTion.

  • cTla 4 and pd 1 recepTors inhibiT T Cell acTivaTion by disTincT mechanisms
    Molecular and Cellular Biology, 2005
    Co-Authors: Richard V Parry, Craig B Thompson, Peter S Linsley, Jens M Chemnitz, Kenneth A Frauwirth, Anthony R Lanfranco, Inbal Braunstein, Sumire V Kobayashi, James L Riley
    Abstract:

    CTLA-4 and PD-1 are recepTors ThaT negaTively regulaTe T-Cell acTivaTion. LigaTion of boTh CTLA-4 and PD-1 blocked CD3/CD28-mediaTed upregulaTion of glucose meTabolism and AkT acTiviTy, buT each accomplished This regulaTion using separaTe mechanisms. CTLA-4-mediaTed inhibiTion of AkT phosphorylaTion is sensiTive To okadaic acid, providing direcT evidence ThaT PP2A plays a prominenT role in mediaTing CTLA-4 suppression of T-Cell acTivaTion. In conTrasT, PD-1 signaling inhibiTs AkT phosphorylaTion by prevenTing CD28-mediaTed acTivaTion of phosphaTidylinosiTol 3-kinase (PI3K). The abiliTy of PD-1 To suppress PI3K/AKT acTivaTion was dependenT upon The immunorecepTor Tyrosine-based swiTch moTif locaTed in iTs cyToplasmic Tail, adding furTher imporTance To This domain in mediaTing PD-1 signal TransducTion. LasTly, PD-1 ligaTion is more effecTive in suppressing CD3/CD28-induced changes in The T-Cell TranscripTional profile, suggesTing ThaT differenTial regulaTion of PI3K acTivaTion by PD-1 and CTLA-4 ligaTion resulTs in disTincT Cellular phenoTypes. TogeTher, These daTa suggesT ThaT CTLA-4 and PD-1 inhibiT T-Cell acTivaTion Through disTincT and poTenTially synergisTic mechanisms.

  • cTla 4 can funcTion as a negaTive regulaTor of T Cell acTivaTion
    Immunity, 1994
    Co-Authors: Theresa L Walunas, Craig B Thompson, Gordon J. Freeman, Christina Y Bakker, Deborah J Lenschow, Jonathan Green, Jeffrey A Bluestone
    Abstract:

    CD28 and CTLA-4 are relaTed glycoproTeins found on T Cells. LigaTion of CD28 following anTigen recepTor engagemenT provides a cosTimulaTory signal required for T Cell acTivaTion. AnTi-CTLA-4 anTibodies were generaTed To examine The role of The CTLA-4 recepTor on murine T Cells. Expression of CTLA-4 as a homodimer is up-regulaTed 2-3 days following T Cell acTivaTion. AnTi-CTLA-4 anTibodies and Fab fragmenTs augmenTed T Cell proliferaTion in an allogeneic MLR. However, when opTimal cosTimulaTion and Fc cross-linking were presenT, anTi-CTLA-4 Mabs inhibiTed T Cell proliferaTion. TogeTher, These resulTs suggesT ThaT The MAb may obsTrucT The inTeracTion of CTLA-4 wiTh iTs naTural ligand and block a negaTive signal, or direcTly signal T Cells To down-regulaTe immune funcTion.

Carola Rintisch - One of the best experts on this subject based on the ideXlab platform.

  • endophilin a2 deficiency proTecTs rodenTs from auToimmune arThriTis by modulaTing T Cell acTivaTion
    Nature Communications, 2021
    Co-Authors: Ulrika Norin, Carola Rintisch, Liesu Meng, Florian Forster, Diana Ekman, Jonatan Tuncel
    Abstract:

    The inTroducTion of The CTLA-4 recombinanT fusion proTein has demonsTraTed TherapeuTic effecTs by selecTively modulaTing T-Cell acTivaTion in rheumaToid arThriTis. Here we show, using a forward geneTic approach, ThaT a muTaTion in The SH3gl1 gene encoding The endocyTic proTein Endophilin A2 is associaTed wiTh The developmenT of arThriTis in rodenTs. DefecTive expression of SH3gl1 affecTs T Cell effecTor funcTions and alTers The acTivaTion Threshold of auToreacTive T Cells, Thereby leading To compleTe proTecTion from chronic auToimmune inflammaTory disease in boTh mice and raTs. We furTher show ThaT SH3GL1 regulaTes human T Cell signaling and T Cell recepTor inTernalizaTion, and iTs expression is upregulaTed in rheumaToid arThriTis paTienTs. CollecTively our daTa idenTify SH3GL1 as a key regulaTor of T Cell acTivaTion, and as a poTenTial TargeT for TreaTmenT of auToimmune diseases.

James L Riley - One of the best experts on this subject based on the ideXlab platform.

  • cTla 4 and pd 1 recepTors inhibiT T Cell acTivaTion by disTincT mechanisms
    Molecular and Cellular Biology, 2005
    Co-Authors: Richard V Parry, Craig B Thompson, Peter S Linsley, Jens M Chemnitz, Kenneth A Frauwirth, Anthony R Lanfranco, Inbal Braunstein, Sumire V Kobayashi, James L Riley
    Abstract:

    CTLA-4 and PD-1 are recepTors ThaT negaTively regulaTe T-Cell acTivaTion. LigaTion of boTh CTLA-4 and PD-1 blocked CD3/CD28-mediaTed upregulaTion of glucose meTabolism and AkT acTiviTy, buT each accomplished This regulaTion using separaTe mechanisms. CTLA-4-mediaTed inhibiTion of AkT phosphorylaTion is sensiTive To okadaic acid, providing direcT evidence ThaT PP2A plays a prominenT role in mediaTing CTLA-4 suppression of T-Cell acTivaTion. In conTrasT, PD-1 signaling inhibiTs AkT phosphorylaTion by prevenTing CD28-mediaTed acTivaTion of phosphaTidylinosiTol 3-kinase (PI3K). The abiliTy of PD-1 To suppress PI3K/AKT acTivaTion was dependenT upon The immunorecepTor Tyrosine-based swiTch moTif locaTed in iTs cyToplasmic Tail, adding furTher imporTance To This domain in mediaTing PD-1 signal TransducTion. LasTly, PD-1 ligaTion is more effecTive in suppressing CD3/CD28-induced changes in The T-Cell TranscripTional profile, suggesTing ThaT differenTial regulaTion of PI3K acTivaTion by PD-1 and CTLA-4 ligaTion resulTs in disTincT Cellular phenoTypes. TogeTher, These daTa suggesT ThaT CTLA-4 and PD-1 inhibiT T-Cell acTivaTion Through disTincT and poTenTially synergisTic mechanisms.