Immunological reviews

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5101MCID_676f0861c771a53fc80e5396 18759931 Jodi L Buckler[author] Buckler, Jodi L[Full Author Name] buckler, jodi l[Author] trying2...
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1600-065X2242008AugImmunological reviewsImmunol RevRegulation of T-cell responses by PTEN.239248239-4810.1111/j.1600-065X.2008.00650.xThe phosphoinositide 3-kinase (PI3K) signaling pathway plays a critical role in the development, activation, and homeostasis of T cells by modulating the expression of survival and mitogenic factors in response to a variety of stimuli. Ligation of the antigen receptor, costimulatory molecules, and cytokine receptors activate PI3K, resulting in the production of the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP(3)). A number of molecules help to regulate the activity of this pathway, including the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10). By limiting the amount of PIP(3) available within the cell, PTEN directly opposes PI3K activity and influences the selection of developing thymocytes as well as the activation requirements of mature T cells. T cells with unchecked PI3K activity, as a result of PTEN deficiency, contribute to the development of both autoimmune disease and lymphoma. This review dissects our current understanding of PI3K and PTEN and discusses why appropriate balance of these molecules is necessary to maintain normal T-cell responses.BucklerJodi LJLDepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.LiuXiaoheXTurkaLaurence ALAengP01 AI043620AINIAID NIH HHSUnited StatesP01 AI043620-010002AINIAID NIH HHSUnited StatesJournal ArticleReview

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0022-176718012008Jan01Journal of immunology (Baltimore, Md. : 1950)J ImmunolCutting edge: requirement for TRAF6 in the induction of T cell anergy.343834-8TRAF6, TNFR-associated factor 6, is a key adaptor downstream from the TNF receptor and TLR superfamily members. T cell-specific deletion of TRAF6 (TRAF6-DeltaT) was recently shown to result in the development of multiorgan inflammatory disease and the resistance of responder T cells to suppression by CD4+CD25+ regulatory T cells. In this study we examined the role of TRAF6 in an additional mechanism of peripheral tolerance, anergy. We have determined that the loss of TRAF6 restores the ability of CD28-/- T cells to proliferate and produce IL-2. Consistent with this, TRAF6-DeltaT T cells were resistant to anergizing signals both in vitro and in vivo. Resistance to anergy was correlated with decreased expression of Cbl-b. These findings reveal that in addition to its role in rendering T cells susceptible to control by CD4+CD25+ regulatory T cells, TRAF6 is essential for the induction of T cell anergy, implicating TRAF6 as a critical mediator of peripheral tolerance.KingCarolyn GCGDepartment of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.BucklerJodi LJLKobayashiTakashiTHannahJeffrey RJRBassettGarrettGKimTaesooTPearceErika LELKimGregory GGGTurkaLaurence ALAChoiYongwonYengAI-43620AINIAID NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., Extramural

United StatesJ Immunol2985117R0022-17670Adaptor Proteins, Signal Transducing0CD4 Antigens0Cblb protein, mouse0Interleukin-2 Receptor alpha Subunit0TNF Receptor-Associated Factor 6EC 2.3.2.27Proto-Oncogene Proteins c-cblIMAdaptor Proteins, Signal TransducinggeneticsmetabolismAnimalsCD4 AntigensanalysisClonal AnergygeneticsInterleukin-2 Receptor alpha SubunitanalysisMiceMice, KnockoutProto-Oncogene Proteins c-cblgeneticsmetabolismT-Lymphocytes, RegulatoryimmunologyTNF Receptor-Associated Factor 6geneticsphysiology20071222902008311902007122290ppublish1809700010.4049/jimmunol.180.1.34180/1/34169828582006102720190516

0022-176717772006Oct01Journal of immunology (Baltimore, Md. : 1950)J ImmunolCutting edge: T cell requirement for CD28 costimulation is due to negative regulation of TCR signals by PTEN.426242664262-6Recent studies suggest that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in the maintenance of self-tolerance. Using T cell-specific PTEN knockout mice (PTENDeltaT), we have identified a novel mechanism by which PTEN regulates T cell tolerance. We found that TCR stimulation alone, without CD28 costimulation, is sufficient to induce hyperactivation of the PI3K pathway, which leads to enhanced IL-2 production by naive PTENDeltaT T cells. Importantly, as a result of this increased response to TCR stimulation, PTENDeltaT CD4(+) T cells no longer require CD28 costimulation for in vitro or in vivo expansion. In fact, unlike wild-type T cells, PTENDeltaT CD4(+) T cells are not anergized by delivery of TCR stimulation alone. These data suggest that by negatively regulating TCR signals, PTEN imposes a requirement for CD28 costimulation, thus defining a novel mechanism for its role in self-tolerance.BucklerJodi LJLDepartment of Medicine, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144, USA.WalshPatrick TPTPorrettPaige MPMChoiYongwonYTurkaLaurence ALAengAI 43620AINIAID NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't

United StatesJ Immunol2985117R0022-17670CD28 Antigens0Interleukin-20Receptors, Antigen, T-CellEC 2.7.1.-Phosphatidylinositol 3-KinasesEC 3.1.3.67PTEN PhosphohydrolaseEC 3.1.3.67Pten protein, mouseIMAnimalsBlotting, WesternCD28 AntigensimmunologymetabolismFlow CytometryImmune ToleranceInterleukin-2biosynthesisMiceMice, KnockoutPTEN PhosphohydrolasedeficiencyimmunologymetabolismPhosphatidylinositol 3-KinasesmetabolismReceptors, Antigen, T-CellimmunologymetabolismT-Lymphocytesimmunologymetabolism2006920902006102890200692090ppublish1698285810.4049/jimmunol.177.7.4262177/7/4262169175402006103020181113

0021-973811692006SepThe Journal of clinical investigationJ Clin InvestPTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs.252125312521-31One of the greatest barriers against harnessing the potential of CD4+ CD25+ Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone. PTEN deficiency does not adversely affect either the thymic development or the function of Tregs, which retain their ability to suppress responder T cells in vitro and prevent colitis in vivo. Conversely, reexpression of PTEN in PTEN-deficient Tregs as well as in activated CD4+ T cells inhibits IL-2-dependent proliferation, confirming PTEN as a negative regulator of IL-2 receptor signaling. These data demonstrate that PTEN regulates the "anergic" response of Tregs to IL-2 in vitro and Treg homeostasis in vivo and indicate that inhibition of PTEN activity may facilitate the expansion of these cells for potential use in cellular immunotherapy.WalshPatrick TPTDepartment of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6144, USA.BucklerJodi LJLZhangJidongJGelmanAndrew EAEDaltonNicole MNMTaylorDevon KDKBensingerSteven JSJHancockWayne WWWTurkaLaurence ALAengP01 AI043620AINIAID NIH HHSUnited StatesAI-43620AINIAID NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't20060817

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1074-76131642002AprImmunityImmunityThe impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells.535546535-46Autoreactive B cells that appear to be inactivated can be found in healthy individuals. In this study, we examined the potential of these anergic cells to become activated. We show that anergy of anti-double-stranded DNA (dsDNA) B cells in BALB/c mice is readily reversed, requiring only the provision of T cell help. We further show that spontaneous loss of anergy among anti-dsDNA B cells in autoimmune lpr/lpr mice occurs in two phases: an abortive initial response to T help followed by full loss of tolerance. Strikingly, the abortive response can be reproduced in nonautoimmune mice when CD4+CD25+ T regulatory cells are administered in conjunction with CD4+ T helper cells, suggesting that loss of B cell tolerance may require both the production of T cell help and the overcoming of T suppression.SeoSu-jeanSJThe Wistar Institute, Philadelphia, PA 19104, USA.FieldsMichele LMLBucklerJodi LJLReedAmy JAJMandik-NayakLauraLNishSimone ASANoelleRandolph JRJTurkaLaurence ALAFinkelmanFred DFDCatonAndrew JAJEriksonJanJengAI 24541AINIAID NIH HHSUnited StatesAI 32137AINIAID NIH HHSUnited StatesAR 49713ARNIAMS NIH HHSUnited StatesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

United StatesImmunity94329181074-76130Antigens, CD0Antigens, Differentiation0B7-1 Antigen0CD28 Antigens0CD40 Antigens0CTLA-4 Antigen0CXCR5 protein, mouse0Ctla4 protein, mouse0Immunoconjugates0Receptors, CXCR50Receptors, Chemokine0Receptors, Cytokine0Receptors, Interleukin-2147205-72-9CD40 Ligand7D0YB67S97Abatacept9007-49-2DNAIMAbataceptAnimalsAntigens, CDAntigens, DifferentiationimmunologyB-LymphocytescytologyimmunologyB7-1 AntigenimmunologyCD28 AntigensimmunologyCD4-Positive T-LymphocytesimmunologyCD40 AntigensimmunologyCD40 LigandimmunologyCTLA-4 AntigenCell DifferentiationClonal AnergyimmunologyDNAimmunologyFemaleImmunoconjugatesLymphocyte ActivationimmunologyMaleMiceMice, Inbred BALB CMice, Inbred MRL lprMice, TransgenicModels, ImmunologicalReceptors, CXCR5Receptors, ChemokineReceptors, CytokinebiosynthesisimmunologyReceptors, Interleukin-2immunologySpleencytologyimmunologyT-Lymphocytes, Helper-Inducerimmunology200242410020025151012002424100ppublish1197087710.1016/s1074-7613(02)00298-4S1074-7613(02)00298-4trying2...
Publications by Jodi L Buckler | LitMetric

Publications by authors named "Jodi L Buckler"

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Regulation of T-cell responses by PTEN.

Jodi L Buckler Xiaohe Liu Laurence A Turka

Immunol Rev

August 2008

The phosphoinositide 3-kinase (PI3K) signaling pathway plays a critical role in the development, activation, and homeostasis of T cells by modulating the expression of survival and mitogenic factors in response to a variety of stimuli. Ligation of the antigen receptor, costimulatory molecules, and cytokine receptors activate PI3K, resulting in the production of the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP(3)). A number of molecules help to regulate the activity of this pathway, including the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10).

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Cutting edge: requirement for TRAF6 in the induction of T cell anergy.

Carolyn G King Jodi L Buckler Takashi Kobayashi Jeffrey R Hannah Garrett Bassett

J Immunol

January 2008

TRAF6, TNFR-associated factor 6, is a key adaptor downstream from the TNF receptor and TLR superfamily members. T cell-specific deletion of TRAF6 (TRAF6-DeltaT) was recently shown to result in the development of multiorgan inflammatory disease and the resistance of responder T cells to suppression by CD4+CD25+ regulatory T cells. In this study we examined the role of TRAF6 in an additional mechanism of peripheral tolerance, anergy.

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Cutting edge: T cell requirement for CD28 costimulation is due to negative regulation of TCR signals by PTEN.

Jodi L Buckler Patrick T Walsh Paige M Porrett Yongwon Choi Laurence A Turka

J Immunol

October 2006

Recent studies suggest that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in the maintenance of self-tolerance. Using T cell-specific PTEN knockout mice (PTENDeltaT), we have identified a novel mechanism by which PTEN regulates T cell tolerance. We found that TCR stimulation alone, without CD28 costimulation, is sufficient to induce hyperactivation of the PI3K pathway, which leads to enhanced IL-2 production by naive PTENDeltaT T cells.

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PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs.

Patrick T Walsh Jodi L Buckler Jidong Zhang Andrew E Gelman Nicole M Dalton

J Clin Invest

September 2006

One of the greatest barriers against harnessing the potential of CD4+ CD25+ Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone.

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The impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells.

Su-jean Seo Michele L Fields Jodi L Buckler Amy J Reed Laura Mandik-Nayak

Immunity

April 2002

Autoreactive B cells that appear to be inactivated can be found in healthy individuals. In this study, we examined the potential of these anergic cells to become activated. We show that anergy of anti-double-stranded DNA (dsDNA) B cells in BALB/c mice is readily reversed, requiring only the provision of T cell help.

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