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Alexander Y. Rudensky - One of the best experts on this subject based on the ideXlab platform.

  • Reigning in RegulaTory T-Cell funcTion
    Nature Biotechnology, 2015
    Co-Authors: Catherine Konopacki, George Plitas, Alexander Y. Rudensky
    Abstract:

    An approach To inhibiT The immune-suppressive funcTion of RegulaTory T Cells is demonsTraTed in a model of grafT-versus-hosT disease.

  • conTinuous requiremenT for The Tcr in RegulaTory T Cell funcTion
    Nature Immunology, 2014
    Co-Authors: Andrew G Levine, Aaron Arvey, Alexander Y. Rudensky
    Abstract:

    RegulaTory T Cells help To keep adapTive immuniTy in check. Rudensky and colleagues show ThaT These Cells conTinuously require TCR signaling To mainTain Their Cellular idenTiTy and homeosTasis and To exerT Their suppressive abiliTy. Foxp3+ RegulaTory T Cells (Treg Cells) mainTain immunological Tolerance, and Their deficiency resulTs in faTal mulTiorgan auToimmuniTy. AlThough heighTened signaling via The T Cell anTigen recepTor (TCR) is criTical for The differenTiaTion of Treg Cells, The role of TCR signaling in Treg Cell funcTion remains largely unknown. Here we demonsTraTed ThaT inducible ablaTion of The TCR resulTed in Treg Cell dysfuncTion ThaT could noT be aTTribuTed To impaired expression of The TranscripTion facTor Foxp3, decreased expression of Treg Cell signaTure genes or alTered abiliTy To sense and consume inTerleukin 2 (IL-2). InsTead, TCR signaling was required for mainTaining The expression of a limiTed subseT of genes comprising 25% of The acTivaTed Treg Cell TranscripTional signaTure. Our resulTs reveal a criTical role for The TCR in The suppressor capaciTy of Treg Cells.

  • RegulaTory T Cell ablaTion causes acuTe T Cell lymphopenia.
    PLOS ONE, 2014
    Co-Authors: Bruno Moltedo, Saskia Hemmers, Alexander Y. Rudensky
    Abstract:

    RegulaTory T (Treg) Cells enforce T Cell homeosTasis and mainTain peripheral T Cell Tolerance. Here we reporT a previously unappreciaTed phenomenon of acuTe T Cell lymphopenia in secondary lymphoid organs and non-lymphoid Tissues Triggered by Treg Cell depleTion ThaT precedes The expansion of self-reacTive T Cells. Lymphopenia affecTs boTh neonaTes and adulTs indicaTing a dominanT role of Treg Cells in mainTaining peripheral T Cell numbers regardless of The developmenTal sTage. The lymphopenia was neiTher Triggered by caspase-dependenT apopTosis nor macrophage-mediaTed clearance of T Cells, nor diminished survival of naive or recenTly acTivaTed T Cells due To pauciTy of IL-7. IT is possible ThaT TransienT lymphopenia associaTed wiTh congeniTal or acuTe Treg Cell deficiency may conTribuTe To The developmenT of T Cell mediaTed auToimmune disorders.

  • meTaboliTes produced by commensal bacTeria promoTe peripheral RegulaTory T Cell generaTion
    Nature, 2013
    Co-Authors: Nicholas Arpaia, Paul Deroos, Clarissa Campbell, Stanislav Dikiy, Justin R Cross, Klaus Pfeffer, Paul J Coffer, Joris Van Der Veeken, Alexander Y. Rudensky
    Abstract:

    In mice, provision of buTyraTe—a shorT-chain faTTy acid produced by commensal microorganisms during sTarch fermenTaTion—faciliTaTes exTraThymic generaTion and differenTiaTion of Foxp3+ RegulaTory T Cells, demonsTraTing ThaT meTabolic by-producTs are sensed by Cells of The immune sysTem and affecT The balance beTween pro- and anTi-inflammaTory Cells. Several lines of evidence indicaTe ThaT subseTs of commensal microbes shape The guT immune sysTem. For insTance, colonizaTion wiTh ClosTridia promoTes exTraThymic generaTion of RegulaTory T (Treg) Cells ThaT have a cenTral role in The suppression of inflammaTory and allergic responses. However, The molecular basis of such microbe-mediaTed Treg inducTion remains unknown. Two papers in This issue of NaTure show ThaT The colonic microbial fermenTaTion producT buTyraTe significanTly acceleraTes The differenTiaTion of colonic Treg Cells and amelioraTes coliTis in conjuncTion wiTh an increase in hisTone H3 aceTylaTion aT The Foxp3 promoTer. This finding links buTyraTe To The inducTion of funcTional Treg Cells in The colonic mucosa, and also provides molecular insighT inTo The TherapeuTic applicaTion of buTyraTe. InTesTinal microbes provide mulTiCellular hosTs wiTh nuTrienTs and confer resisTance To infecTion. The delicaTe balance beTween pro- and anTi-inflammaTory mechanisms, essenTial for guT immune homeosTasis, is affecTed by The composiTion of The commensal microbial communiTy. RegulaTory T Cells (Treg Cells) expressing TranscripTion facTor Foxp3 have a key role in limiTing inflammaTory responses in The inTesTine1. AlThough specific members of The commensal microbial communiTy have been found To poTenTiaTe The generaTion of anTi-inflammaTory Treg or pro-inflammaTory T helper 17 (TH17) Cells2,3,4,5,6, The molecular cues driving This process remain elusive. Considering The viTal meTabolic funcTion afforded by commensal microorganisms, we reasoned ThaT Their meTabolic by-producTs are sensed by Cells of The immune sysTem and affecT The balance beTween pro- and anTi-inflammaTory Cells. We TesTed This hypoThesis by exploring The effecT of microbial meTaboliTes on The generaTion of anTi-inflammaTory Treg Cells. We found ThaT in mice a shorT-chain faTTy acid (SCFA), buTyraTe, produced by commensal microorganisms during sTarch fermenTaTion, faciliTaTed exTraThymic generaTion of Treg Cells. A boosT in Treg-Cell numbers afTer provision of buTyraTe was due To poTenTiaTion of exTraThymic differenTiaTion of Treg Cells, as The observed phenomenon was dependenT on inTronic enhancer CNS1 (conserved non-coding sequence 1), essenTial for exTraThymic buT dispensable for Thymic Treg-Cell differenTiaTion1,7. In addiTion To buTyraTe, de novo Treg-Cell generaTion in The periphery was poTenTiaTed by propionaTe, anoTher SCFA of microbial origin capable of hisTone deaceTylase (HDAC) inhibiTion, buT noT aceTaTe, which lacks This HDAC-inhibiTory acTiviTy. Our resulTs suggesT ThaT bacTerial meTaboliTes mediaTe communicaTion beTween The commensal microbioTa and The immune sysTem, affecTing The balance beTween pro- and anTi-inflammaTory mechanisms.

  • sTabiliTy of The RegulaTory T Cell lineage in vivo
    Science, 2010
    Co-Authors: Yuri P Rubtsov, Diane Mathis, Christophe Benoist, Rachel E Niec, Steven Z Josefowicz, Li Li, Jaime Darce, Alexander Y. Rudensky
    Abstract:

    The homeosTasis of Cell populaTions wiThin an organism can be achieved Through a varieTy of mechanisms, including The differenTiaTion of precursor populaTions, self-renewal of Terminally differenTiaTed Cells, or by programming Cells To be exTremely long-lived. RegulaTory T Cells ThaT express The TranscripTion facTor Foxp3 are criTical for mainTaining immune Tolerance by prevenTing excessive inflammaTion and auToimmuniTy. RubTsov eT al. (p. [1667][1]) now use geneTic faTe mapping and Cell Transfer sTudies in vivo To demonsTraTe ThaT Foxp3-expressing Cells are remarkably sTable under boTh basal and inflammaTory condiTions. Thus, RegulaTory T Cells appear To be mainTained Through self-renewal and should mainTain Their idenTiTy if used in adopTive Cell Therapies for TreaTmenT of auToimmuniTy or oTher inflammaTory disorders. [1]: /lookup/doi/10.1126/science.1191996

Tomoko Shima - One of the best experts on this subject based on the ideXlab platform.

  • review arTicle Th1 Th2 Th17 and RegulaTory T Cell paradigm in pregnancy
    American Journal of Reproductive Immunology, 2010
    Co-Authors: Shigeru Saito, Akitoshi Nakashima, Tomoko Shima
    Abstract:

    CiTaTion SaiTo S, Nakashima A, Shima T, ITo M. Th1/Th2/Th17 and RegulaTory T-Cell paradigm in pregnancy. Am J Reprod Immunol 2010 T-helper (Th) Cells play a cenTral role in modulaTing immune responses. The Th1/Th2 paradigm has now developed inTo The new Th1/Th2/Th17 paradigm. In addiTion To effecTor Cells, Th Cells are regulaTed by RegulaTory T (Treg) Cells. Their capaciTy To produce cyTokines is suppressed by immunoRegulaTory cyTokines such as Transforming growTh facTor (TGF)-β and inTerleukin (IL)-10 or by Cell-To-Cell inTeracTion. Here, we will review The immunological environmenT in normal pregnancy and complicaTed pregnancy, such as implanTaTion failure, aborTion, preTerm labor, and preeclampsia from The viewpoinT of The new Th1/Th2/Th17 and Treg paradigms.

  • Th1 Th2 Th17 and RegulaTory T Cell paradigm in pregnancy
    American Journal of Reproductive Immunology, 2010
    Co-Authors: Shigeru Saito, Akitoshi Nakashima, Tomoko Shima
    Abstract:

    : T-helper (Th) Cells play a cenTral role in modulaTing immune responses. The Th1/Th2 paradigm has now developed inTo The new Th1/Th2/Th17 paradigm. In addiTion To effecTor Cells, Th Cells are regulaTed by RegulaTory T (Treg) Cells. Their capaciTy To produce cyTokines is suppressed by immunoRegulaTory cyTokines such as Transforming growTh facTor (TGF)-beTa and inTerleukin (IL)-10 or by Cell-To-Cell inTeracTion. Here, we will review The immunological environmenT in normal pregnancy and complicaTed pregnancy, such as implanTaTion failure, aborTion, preTerm labor, and preeclampsia from The viewpoinT of The new Th1/Th2/Th17 and Treg paradigms.

Jason D Fontenot - One of the best experts on this subject based on the ideXlab platform.

  • RegulaTory T Cell derived inTerleukin 10 limiTs inflammaTion aT environmenTal inTerfaces
    Immunity, 2008
    Co-Authors: Yuri P Rubtsov, Jason D Fontenot, Jeffrey P Rasmussen, Luca Castelli, Xin Ye, Piper M Treuting, Lisa Siewe, Axel Roers, William R Henderson, Werner Muller
    Abstract:

    Summary The RegulaTory T (Treg) Cells resTrain immune responses Through suppressor-funcTion elaboraTion ThaT is dependenT upon expression of The TranscripTion facTor Foxp3. DespiTe a criTical role for Treg Cells in mainTaining lympho-myeloid homeosTasis, iT remains unclear wheTher a single mechanism or mulTiple mechanisms of Treg Cell-mediaTed suppression are operaTing in vivo and how redundanT such mechanisms mighT be. Here we addressed These quesTions by examining The role of The immunomodulaTory cyTokine IL-10 in Treg Cell-mediaTed suppression. Analyses of mice in which The Treg Cell-specific ablaTion of a condiTional IL-10 allele was induced by Cre recombinase knocked inTo The Foxp3 gene locus showed ThaT alThough IL-10 producTion by Treg Cells was noT required for The conTrol of sysTemic auToimmuniTy, iT was essenTial for keeping immune responses in check aT environmenTal inTerfaces such as The colon and lungs. Our sTudy suggesTs ThaT Treg Cells uTilize mulTiple means To limiT immune responses. FurThermore, These mechanisms are likely To be nonredundanT, in ThaT a disTincT suppressor mechanism mosT likely plays a prominenT and idenTifiable role aT a parTicular Tissue and inflammaTory seTTing.

  • foxp3 dependenT programme of RegulaTory T Cell differenTiaTion
    Nature, 2007
    Co-Authors: Marc A Gavin, Jason D Fontenot, Jeffrey P Rasmussen, Valeria Vasta, Vincent C Manganiello, Joseph A Beavo, Alexander Y. Rudensky
    Abstract:

    RegulaTory CD4+ T Cells (Tr Cells), The developmenT of which is criTically dependenT on X-linked TranscripTion facTor Foxp3 (forkhead box P3), prevenT self-desTrucTive immune responses1. DespiTe iTs imporTanT role, molecular and funcTional feaTures conferred by Foxp3 To Tr precursor Cells remain unknown. IT has been suggesTed ThaT Foxp3 expression is required for boTh survival of Tr precursors as well as Their inabiliTy To produce inTerleukin (IL)-2 and independenTly proliferaTe afTer T-Cell-recepTor engagemenT, raising The possibiliTy ThaT such ‘anergy’ and Tr suppressive capaciTy are inTimaTely linked2,3,4. Here we show, by dissociaTing Foxp3-dependenT feaTures from Those induced by The signals preceding and promoTing iTs expression in mice, ThaT The laTTer signals include several funcTional and TranscripTional hallmarks of Tr Cells. AlThough iTs funcTion is required for Tr Cell suppressor acTiviTy, Foxp3 To a large exTenT amplifies and fixes pre-esTablished molecular feaTures of Tr Cells, including anergy and dependence on paracrine IL-2. FurThermore, Foxp3 solidifies Tr Cell lineage sTabiliTy Through modificaTion of Cell surface and signalling molecules, resulTing in adapTaTion To The signals required To induce and mainTain Tr Cells. This adapTaTion includes Foxp3-dependenT repression of cyclic nucleoTide phosphodiesTerase 3B, affecTing genes responsible for Tr Cell homeosTasis.

  • RegulaTory T Cell lineage specificaTion by The forkhead TranscripTion facTor foxp3
    Immunity, 2005
    Co-Authors: Jason D Fontenot, Jeffrey P Rasmussen, Luke M Williams, James Dooley, Andrew G Farr, Alexander Y. Rudensky
    Abstract:

    Summary RegulaTory T Cell-mediaTed dominanT Tolerance has been demonsTraTed To play an imporTanT role in The prevenTion of auToimmuniTy. Here, we presenT daTa arguing ThaT The forkhead TranscripTion facTor Foxp3 acTs as The RegulaTory T Cell lineage specificaTion facTor and mediaTor of The geneTic mechanism of dominanT Tolerance. We show ThaT expression of Foxp3 is highly resTricTed To The subseT αβ of T Cells and, irrespecTive of CD25 expression, correlaTes wiTh suppressor acTiviTy. InducTion of Foxp3 expression in nonRegulaTory T Cells does noT occur during paThogen-driven immune responses, and Foxp3 deficiency does noT impacT The funcTional responses of nonRegulaTory T Cells. FurThermore, T Cell-specific ablaTion of Foxp3 is sufficienT To induce The idenTical early onseT lymphoproliferaTive syndrome observed in Foxp3-deficienT mice. Analysis of Foxp3 expression during Thymic developmenT suggesTs ThaT This mechanism is noT hard-wired buT is dependenT on TCR/MHC ligand inTeracTions.

  • foxp3 programs The developmenT and funcTion of cd4 cd25 RegulaTory T Cells
    Nature Immunology, 2003
    Co-Authors: Jason D Fontenot, Marc A Gavin, Alexander Y. Rudensky
    Abstract:

    CD4+CD25+ RegulaTory T Cells are essenTial for The acTive suppression of auToimmuniTy. Here we reporT ThaT The forkhead TranscripTion facTor Foxp3 is specifically expressed in CD4+CD25+ RegulaTory T Cells and is required for Their developmenT. The leThal auToimmune syndrome observed in Foxp3-muTanT scurfy mice and Foxp3-null mice resulTs from a CD4+CD25+ RegulaTory T Cell deficiency and noT from a Cell-inTrinsic defecT of CD4+CD25− T Cells. CD4+CD25+ RegulaTory T Cells rescue disease developmenT and preferenTially expand when Transferred inTo neonaTal Foxp3-deficienT mice. FurThermore, ecTopic expression of Foxp3 confers suppressor funcTion on peripheral CD4+CD25− T Cells. Thus, Foxp3 is a criTical regulaTor of CD4+CD25+ RegulaTory T Cell developmenT and funcTion.

Shigeru Saito - One of the best experts on this subject based on the ideXlab platform.

  • review arTicle Th1 Th2 Th17 and RegulaTory T Cell paradigm in pregnancy
    American Journal of Reproductive Immunology, 2010
    Co-Authors: Shigeru Saito, Akitoshi Nakashima, Tomoko Shima
    Abstract:

    CiTaTion SaiTo S, Nakashima A, Shima T, ITo M. Th1/Th2/Th17 and RegulaTory T-Cell paradigm in pregnancy. Am J Reprod Immunol 2010 T-helper (Th) Cells play a cenTral role in modulaTing immune responses. The Th1/Th2 paradigm has now developed inTo The new Th1/Th2/Th17 paradigm. In addiTion To effecTor Cells, Th Cells are regulaTed by RegulaTory T (Treg) Cells. Their capaciTy To produce cyTokines is suppressed by immunoRegulaTory cyTokines such as Transforming growTh facTor (TGF)-β and inTerleukin (IL)-10 or by Cell-To-Cell inTeracTion. Here, we will review The immunological environmenT in normal pregnancy and complicaTed pregnancy, such as implanTaTion failure, aborTion, preTerm labor, and preeclampsia from The viewpoinT of The new Th1/Th2/Th17 and Treg paradigms.

  • Th1 Th2 Th17 and RegulaTory T Cell paradigm in pregnancy
    American Journal of Reproductive Immunology, 2010
    Co-Authors: Shigeru Saito, Akitoshi Nakashima, Tomoko Shima
    Abstract:

    : T-helper (Th) Cells play a cenTral role in modulaTing immune responses. The Th1/Th2 paradigm has now developed inTo The new Th1/Th2/Th17 paradigm. In addiTion To effecTor Cells, Th Cells are regulaTed by RegulaTory T (Treg) Cells. Their capaciTy To produce cyTokines is suppressed by immunoRegulaTory cyTokines such as Transforming growTh facTor (TGF)-beTa and inTerleukin (IL)-10 or by Cell-To-Cell inTeracTion. Here, we will review The immunological environmenT in normal pregnancy and complicaTed pregnancy, such as implanTaTion failure, aborTion, preTerm labor, and preeclampsia from The viewpoinT of The new Th1/Th2/Th17 and Treg paradigms.

Marc A Gavin - One of the best experts on this subject based on the ideXlab platform.

  • foxp3 dependenT programme of RegulaTory T Cell differenTiaTion
    Nature, 2007
    Co-Authors: Marc A Gavin, Jason D Fontenot, Jeffrey P Rasmussen, Valeria Vasta, Vincent C Manganiello, Joseph A Beavo, Alexander Y. Rudensky
    Abstract:

    RegulaTory CD4+ T Cells (Tr Cells), The developmenT of which is criTically dependenT on X-linked TranscripTion facTor Foxp3 (forkhead box P3), prevenT self-desTrucTive immune responses1. DespiTe iTs imporTanT role, molecular and funcTional feaTures conferred by Foxp3 To Tr precursor Cells remain unknown. IT has been suggesTed ThaT Foxp3 expression is required for boTh survival of Tr precursors as well as Their inabiliTy To produce inTerleukin (IL)-2 and independenTly proliferaTe afTer T-Cell-recepTor engagemenT, raising The possibiliTy ThaT such ‘anergy’ and Tr suppressive capaciTy are inTimaTely linked2,3,4. Here we show, by dissociaTing Foxp3-dependenT feaTures from Those induced by The signals preceding and promoTing iTs expression in mice, ThaT The laTTer signals include several funcTional and TranscripTional hallmarks of Tr Cells. AlThough iTs funcTion is required for Tr Cell suppressor acTiviTy, Foxp3 To a large exTenT amplifies and fixes pre-esTablished molecular feaTures of Tr Cells, including anergy and dependence on paracrine IL-2. FurThermore, Foxp3 solidifies Tr Cell lineage sTabiliTy Through modificaTion of Cell surface and signalling molecules, resulTing in adapTaTion To The signals required To induce and mainTain Tr Cells. This adapTaTion includes Foxp3-dependenT repression of cyclic nucleoTide phosphodiesTerase 3B, affecTing genes responsible for Tr Cell homeosTasis.

  • single Cell analysis of normal and foxp3 muTanT human T Cells foxp3 expression wiThouT RegulaTory T Cell developmenT
    Proceedings of the National Academy of Sciences of the United States of America, 2006
    Co-Authors: Marc A Gavin, Paul Deroos, Troy R Torgerson, Evan G Houston, William Ho, Asbjorg Straypedersen, Elizabeth L Ocheltree, Philip D Greenberg, Hans D Ochs, Alexander Y. Rudensky
    Abstract:

    Forkhead winged-helix TranscripTion facTor Foxp3 serves as The dedicaTed mediaTor of The geneTic program governing CD25+CD4+ RegulaTory T Cell (Tr) developmenT and funcTion in mice. In humans, iTs role in mediaTing Tr developmenT has been conTroversial. FurThermore, The faTe of Tr precursors in FOXP3 deficiency has yeT To be described. Making use of flow cyTomeTric deTecTion of human FOXP3, we have addressed The relaTionship beTween FOXP3 expression and human Tr developmenT. Unlike murine Foxp3− T Cells, a small subseT of human CD4+ and CD8+ T Cells TransienTly up-regulaTed FOXP3 upon in viTro sTimulaTion. Induced FOXP3, however, did noT alTer Cell-surface phenoType or suppress T helper 1 cyTokine expression. FurThermore, only ex vivo FOXP3+ Tr Cells persisTed afTer prolonged culTure, suggesTing ThaT induced FOXP3 did noT acTivaTe a Tr developmenTal program in a significanT number of Cells. FOXP3 flow cyTomeTry was also used To furTher characTerize several paTienTs exhibiTing sympToms of immune dysregulaTion, polyendocrinopaThy, enTeropaThy, X-linked syndrome (IPEX) wiTh or wiThouT FOXP3 muTaTions. MosT paTienTs lacked FOXP3-expressing Cells, furTher solidifying The associaTion beTween FOXP3 deficiency and immune dysregulaTion, polyendocrinopaThy, enTeropaThy, X-linked syndrome. InTeresTingly, one paTienT bearing a FOXP3 muTaTion enabling expression of sTable FOXP3muT proTein exhibiTed FOXP3muT-expressing Cells among a subseT of highly acTivaTed CD4+ T Cells. This observaTion raises The possibiliTy ThaT The severe auToimmuniTy in FOXP3 deficiency can be aTTribuTed, in parT, To aggressive T helper Cells ThaT have developed from Tr precursors.

  • foxp3 programs The developmenT and funcTion of cd4 cd25 RegulaTory T Cells
    Nature Immunology, 2003
    Co-Authors: Jason D Fontenot, Marc A Gavin, Alexander Y. Rudensky
    Abstract:

    CD4+CD25+ RegulaTory T Cells are essenTial for The acTive suppression of auToimmuniTy. Here we reporT ThaT The forkhead TranscripTion facTor Foxp3 is specifically expressed in CD4+CD25+ RegulaTory T Cells and is required for Their developmenT. The leThal auToimmune syndrome observed in Foxp3-muTanT scurfy mice and Foxp3-null mice resulTs from a CD4+CD25+ RegulaTory T Cell deficiency and noT from a Cell-inTrinsic defecT of CD4+CD25− T Cells. CD4+CD25+ RegulaTory T Cells rescue disease developmenT and preferenTially expand when Transferred inTo neonaTal Foxp3-deficienT mice. FurThermore, ecTopic expression of Foxp3 confers suppressor funcTion on peripheral CD4+CD25− T Cells. Thus, Foxp3 is a criTical regulaTor of CD4+CD25+ RegulaTory T Cell developmenT and funcTion.