2017
Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme
Goods BA, Hernandez AL, Lowther DE, Lucca LE, Lerner BA, Gunel M, Raddassi K, Coric V, Hafler DA, Love JC. Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme. PLOS ONE 2017, 12: e0181538. PMID: 28880903, PMCID: PMC5589094, DOI: 10.1371/journal.pone.0181538.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsPD-1 expressionEffector T cellsPD-1Effector cellsGlioblastoma multiformeCheckpoint inhibitorsTim-3T cellsHealthy subjectsCell death protein 1Features of exhaustionDeath protein 1T cell compartmentContext of GBMRecovery of functionCD4 effectorsCD4 cellsRNA sequencingTreatment of cancerHealthy donorsGBM patientsBrain cancerCD4Tumors
2013
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013, 496: 518-522. PMID: 23467095, PMCID: PMC3746493, DOI: 10.1038/nature11868.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedEncephalomyelitis, Autoimmune, ExperimentalGene SilencingGranulocyte-Macrophage Colony-Stimulating FactorHumansImmediate-Early ProteinsInterleukin-2MAP Kinase Signaling SystemMiceMice, Inbred C57BLP38 Mitogen-Activated Protein KinasesPhenotypeProtein Serine-Threonine KinasesSodium Chloride, DietaryTh17 CellsTranscription FactorsTumor Necrosis Factor-alpha
2009
Engineered Interleukin-2 Antagonists for the Inhibition of Regulatory T Cells
Liu DV, Maier LM, Hafler DA, Wittrup KD. Engineered Interleukin-2 Antagonists for the Inhibition of Regulatory T Cells. Journal Of Immunotherapy 2009, 32: 887-894. PMID: 19816193, PMCID: PMC4078882, DOI: 10.1097/cji.0b013e3181b528da.Peer-Reviewed Original ResearchConceptsIL-2 receptorRegulatory T cellsWild-type IL-2IL-2T cellsIL-2 analogHigh regulatory T cellsIL-2 receptor alphaRegulatory T-cell suppressionInterleukin-2 antagonistsAntitumor immune responseT cell suppressionIL-2 receptor alpha subunitT cell growthT cell linesTreg inhibitionImmunosuppressive effectsCancer patientsSimilar efficacyImmune responseReceptor alpha subunitCell suppressionReceptor alphaAlpha subunitHuman interleukinSoluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses
Maier LM, Anderson DE, Severson CA, Baecher-Allan C, Healy B, Liu DV, Wittrup KD, De Jager PL, Hafler DA. Soluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses. The Journal Of Immunology 2009, 182: 1541-1547. PMID: 19155502, PMCID: PMC3992946, DOI: 10.4049/jimmunol.182.3.1541.Peer-Reviewed Original ResearchConceptsMultiple sclerosisIL-2 receptorMS subjectsHealthy controlsOrgan-specific autoimmune disordersChronic systemic inflammationType 1 diabetesT cell proliferationMultiple sclerosis subjectsStrong genetic factorIL-2 signalingSIL-2RaSystemic inflammationAutoimmune disordersImmunological perturbationsAutoimmune diseasesIL-2RAControl subjectsMS casesSerum concentrationsDisease onsetSpecific allelic variantsImmune responseAggressive formDisease risk
2003
In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis
Schmied M, Duda PW, Krieger JI, Trollmo C, Hafler DA. In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis. Clinical Immunology 2003, 106: 163-174. PMID: 12706402, DOI: 10.1016/s1521-6616(03)00020-2.Peer-Reviewed Original ResearchConceptsGA-reactive T cellsT cell reactivityT cellsRR-MSMultiple sclerosisCell reactivityT cell peripheral toleranceTh2-type T cellsT cell frequenciesMonths of treatmentT cell hyporesponsivenessT cell populationsT cell nonresponsivenessT cell anergyHyporesponsive T cellsMechanism of actionMyelin antigensGlatiramer acetatePeripheral toleranceCell hyporesponsivenessPeripheral bloodClonal eliminationIL-2Cell anergySubcutaneous administrationCD4+CD25+ Regulatory Cells from Human Peripheral Blood Express Very High Levels of CD25 Ex Vivo
Baecher‐Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25+ Regulatory Cells from Human Peripheral Blood Express Very High Levels of CD25 Ex Vivo. Novartis Foundation Symposia 2003, 252: 67-91. PMID: 14609213, DOI: 10.1002/0470871628.ch6.Peer-Reviewed Original ResearchConceptsT cellsRegulatory cellsPD-1/PD-L1 interactionLigand PD-L1Responder T cellsPD-L1 interactionContact-dependent mannerCo-culture assaysCTLA4 blockadeRegulatory populationPD-1PD-L1HLA-DRMultiple surface antigensCytokine secretionCD45RA expressionSurface antigenEx vivoLevel of expressionModest inductionSuppressive characteristicsFunctional activityHigh levelsCD25CD45RO
2001
CD4+CD25high Regulatory Cells in Human Peripheral Blood
Baecher-Allan C, Brown J, Freeman G, Hafler D. CD4+CD25high Regulatory Cells in Human Peripheral Blood. The Journal Of Immunology 2001, 167: 1245-1253. PMID: 11466340, DOI: 10.4049/jimmunol.167.3.1245.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAntigens, CDAntigens, DifferentiationB7-1 AntigenB7-H1 AntigenBlood ProteinsCD4 AntigensCD4-Positive T-LymphocytesCells, CulturedCoculture TechniquesCTLA-4 AntigenHLA-DR AntigensHumansImmunoconjugatesImmunosuppressive AgentsInterleukin-2KineticsLeukocyte Common AntigensLymphocyte ActivationLymphocyte CountMembrane GlycoproteinsPeptidesReceptors, Antigen, T-CellReceptors, Interleukin-2RNA, MessengerSignal TransductionT-Lymphocyte SubsetsConceptsRegulatory T cellsRegulatory cellsT cellsPD-1/PD-L1Regulatory CD4 T cellsAnti-CD3 stimulusCD4 T cellsHuman autoimmune disordersMultiorgan autoimmune diseasePeripheral lymphoid tissuesRegulatory cell functionIL-2 receptorPD-L1 receptorCirculation of humansHuman peripheral bloodContact-dependent mannerNeonatal day 3B7 pathwayPD-L1Regulatory populationAutoimmune disordersAutoimmune diseasesPeripheral bloodResponder cellsIL-2Uncoupling p70s6 Kinase Activation and Proliferation: Rapamycin-Resistant Proliferation of Human CD8+ T Lymphocytes
Slavik J, Lim D, Burakoff S, Hafler D. Uncoupling p70s6 Kinase Activation and Proliferation: Rapamycin-Resistant Proliferation of Human CD8+ T Lymphocytes. The Journal Of Immunology 2001, 166: 3201-3209. PMID: 11207273, DOI: 10.4049/jimmunol.166.5.3201.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalCD2 AntigensCD28 AntigensCD3 ComplexCD8 AntigensCD8-Positive T-LymphocytesCell Line, TransformedClone CellsDose-Response Relationship, DrugDose-Response Relationship, ImmunologicDrug ResistanceEnzyme ActivationEpitopes, T-LymphocyteHLA-A AntigensHumansImmunosuppressive AgentsInterleukin-2Lymphocyte ActivationMajor Histocompatibility ComplexModels, ImmunologicalRibosomal Protein S6 KinasesSirolimusT-Lymphocyte SubsetsConceptsT cell clonesT cellsEffect of rapamycinHuman T cell responsesPeripheral blood T cellsCell clonesHeterogeneous proliferative responsesT cell responsesBlood T cellsT cell proliferationSpecific costimulatory signalsGraft infiltrationResistant proliferationInhibition of AgGraft rejectionHuman CD8IL-2RT lymphocytesProliferative responseCostimulatory signalsCell responsesPresence of rapamycinCell proliferationRapamycinProliferation
1999
Differential responses of invariant V alpha 24J alpha Q T cells and MHC class II-restricted CD4+ T cells to dexamethasone.
Milner J, Kent S, Ashley T, Wilson S, Strominger J, Hafler D. Differential responses of invariant V alpha 24J alpha Q T cells and MHC class II-restricted CD4+ T cells to dexamethasone. The Journal Of Immunology 1999, 163: 2522-9. PMID: 10452989, DOI: 10.4049/jimmunol.163.5.2522.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAntibodies, BlockingAntibodies, MonoclonalAntigens, CD1Antigens, CD1dAntigens, Differentiation, B-LymphocyteApoptosisAutocrine CommunicationCD3 ComplexCD4-Positive T-LymphocytesClone CellsDexamethasoneDose-Response Relationship, ImmunologicFas ReceptorHistocompatibility Antigens Class IIHumansImmunosuppressive AgentsInterleukin-2Lymphocyte ActivationReceptors, Antigen, T-Cell, alpha-betaSignal TransductionT-Lymphocyte SubsetsConceptsActivation-induced cell deathT cell clonesT cellsTCR signal strengthCell clonesAutocrine IL-2 productionNK T cellsT cell responsesT cell subsetsInhibition of CD4Anti-CD3 stimulationT cell proliferationEffect of dexamethasoneMHC class IIIL-2 productionPresence of dexamethasoneExogenous corticosteroidsCell subsetsImmunomodulatory consequencesDexamethasone treatmentImmune responseCD4High dosesLow dosesCell responses
1998
Myelin basic protein reactive Th2 T cells are found in acute disseminated encephalomyelitis
Pohl-Koppe A, Burchett S, Thiele E, Hafler D. Myelin basic protein reactive Th2 T cells are found in acute disseminated encephalomyelitis. Journal Of Neuroimmunology 1998, 91: 19-27. PMID: 9846815, DOI: 10.1016/s0165-5728(98)00125-8.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, ViralAutoimmunityChildChild, PreschoolDemyelinating DiseasesEncephalomyelitis, Acute DisseminatedEncephalomyelitis, Autoimmune, ExperimentalEpitopesFemaleHerpes ZosterHerpesvirus 3, HumanHumansInfantInterferon-gammaInterleukin-2Interleukin-4MaleMyelin Basic ProteinT-LymphocytesConceptsAcute disseminated encephalomyelitisMBP-reactive T cell linesCentral nervous systemT cellsIL-4T cell linesDisseminated encephalomyelitisSignificant IFN-gamma secretionMyelin-reactive T cellsIFN-gamma secretionIL-4 secretionTh2 T cellsCell linesAutoimmune diseasesPredominant cytokineNormal subjectsSpontaneous recoveryNervous systemPatientsEncephalomyelitisCytokinesSecretionRecovery phaseCellsSubjects
1996
Induction of anergy in CD8 T cells by B cell presentation of antigen.
Höllsberg P, Batra V, Dressel A, Hafler DA. Induction of anergy in CD8 T cells by B cell presentation of antigen. The Journal Of Immunology 1996, 157: 5269-76. PMID: 8955172, DOI: 10.4049/jimmunol.157.12.5269.Peer-Reviewed Original ResearchMeSH KeywordsAntigen-Presenting CellsB-LymphocytesB7-1 AntigenCD40 LigandCD8-Positive T-LymphocytesCell LineClonal AnergyCytotoxicity, ImmunologicGene ExpressionHumansImmunologic MemoryInterleukin-2Lymphocyte ActivationMembrane GlycoproteinsReceptors, Antigen, T-CellSignal TransductionTranscription, GeneticConceptsCD8 T cellsT cell clonesInduction of anergyT cellsB cellsMononuclear cellsB7-1Cell clonesAg stimulationAnergic CD8 T cellsPeptide-pulsed B cellsPeptide-pulsed target cellsCD4 T-cell clonesCD8 T cell clonesSecondary Ag challengeExogenous IL-2B7-2 costimulationB cell presentationT cell anergyIL-2 secretionNormal proliferative responseIL-2 mRNA transcriptionT cell stimulationEarly tyrosine phosphorylationAdequate costimulationHTLV-I-induced T-cell activation.
Buckle GJ, Hafler DA, Höllsberg P. HTLV-I-induced T-cell activation. JAIDS Journal Of Acquired Immune Deficiency Syndromes 1996, 13 Suppl 1: s107-13. PMID: 8797712, DOI: 10.1097/00042560-199600001-00018.Peer-Reviewed Original ResearchConceptsT cell activationT cellsUninfected T cellsT cell interactionsMyelopathy/tropical spastic paraparesisHuman T-cell lymphotropic virus type ILymphotropic virus type ITropical spastic paraparesisInfected T cellsT cell clonesIL-2 productionInterleukin-2 productionVirus type ISpastic paraparesisSpontaneous proliferationCD28 pathwayGeneralized activationCostimulatory signalsImmune systemSeparate mechanismsHTLVProlonged stateType IActivationCells
1995
A Review of T‐Cell Receptors in Multiple Sclerosis: Clonal Expansion and Persistence of Human T‐Cells Specific for an Immunodominant Myelin Basic Protein Peptidea
WUCHERPFENNIG K, HAFLER D. A Review of T‐Cell Receptors in Multiple Sclerosis: Clonal Expansion and Persistence of Human T‐Cells Specific for an Immunodominant Myelin Basic Protein Peptidea. Annals Of The New York Academy Of Sciences 1995, 756: 241-258. PMID: 7544075, DOI: 10.1111/j.1749-6632.1995.tb44522.x.Peer-Reviewed Original ResearchConceptsImmunodominant MBP peptidesT cell clonesMBP peptidesImmune responseNormal subjectsMBP-specific T cell clonesIndividual multiple sclerosis patientsTCR beta-chain usageMBP-specific T cellsTCR V beta chainsDR2 haplotypeSpecific T cell clonesBeta-chain usageT cell responsesAntigen-specific therapyMultiple sclerosis patientsSpecific T cellsDifferent T-cell linesT Cells SpecificIdentical TCR sequencesT cell receptorT cell linesAlpha-chain rearrangementMyelin antigensMS patientsInhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis.
Balashov KE, Khoury SJ, Hafler DA, Weiner HL. Inhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis. Journal Of Clinical Investigation 1995, 95: 2711-2719. PMID: 7769110, PMCID: PMC295954, DOI: 10.1172/jci117973.Peer-Reviewed Original ResearchConceptsAutologous mixed lymphocyte reactionProgressive multiple sclerosisChronic progressive multiple sclerosisInduction of CD8Tact cellsMultiple sclerosisT cellsHuman CD8Suppressive propertiesAutologous T cellsRelapsing-remitting MST cell responsesHuman autoimmune diseasesMixed lymphocyte reactionGM-CSF antibodySuppressive CD8Autologous antigenLymphocyte reactionAutoimmune diseasesBeta antibodyGamma antibodyCD8Proliferative responseSpecific cytokinesNormal controls
1994
Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide.
Wucherpfennig KW, Zhang J, Witek C, Matsui M, Modabber Y, Ota K, Hafler DA. Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide. The Journal Of Immunology 1994, 152: 5581-92. PMID: 7514641, DOI: 10.4049/jimmunol.152.11.5581.Peer-Reviewed Original ResearchConceptsT cellsNormal subjectsImmunodominant myelin basic protein peptideMBP-specific T cell linesDR2 haplotypeSpecific T cell clonesTCR beta-chain sequencesReactive T cellsT cell responsesHLA-DR moleculesT cell clonesIdentical TCR sequencesMyelin basic protein peptideIL-2 stimulationT cell linesHuman T cellsAlpha-chain rearrangementMyelin basic proteinMultiple sclerosisBeta chain sequencesTCR rearrangementsPatientsCell responsesTCR alphaTCR sequencesIncreased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.
Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. Journal Of Experimental Medicine 1994, 179: 973-984. PMID: 7509366, PMCID: PMC2191414, DOI: 10.1084/jem.179.3.973.Peer-Reviewed Original ResearchConceptsMyelin-reactive T cellsFrequency of MBPMBP-reactive T cell linesMBP-reactive T cellsMyelin basic proteinT cellsCerebrospinal fluidT cell linesMS patientsProteolipid proteinPLP-reactive T cellsNormal individualsFrequency of interleukinAutoreactive T cellsPathogenesis of MSMultiple sclerosis patientsIL-2-responsive cellsRIL-2 stimulationCentral nervous systemCell linesBasic proteinSclerosis patientsMultiple sclerosisPeripheral bloodPathogenic role
1992
Characterization of HTLV-I in vivo infected T cell clones. IL-2-independent growth of nontransformed T cells.
Höllsberg P, Wucherpfennig KW, Ausubel LJ, Calvo V, Bierer BE, Hafler DA. Characterization of HTLV-I in vivo infected T cell clones. IL-2-independent growth of nontransformed T cells. The Journal Of Immunology 1992, 148: 3256-63. PMID: 1374452, DOI: 10.4049/jimmunol.148.10.3256.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, Differentiation, T-LymphocyteBase SequenceCD3 ComplexClone CellsCyclosporineHTLV-I InfectionsHumansInterleukin-2Lymphocyte ActivationMolecular Sequence DataPolyenesReceptors, Antigen, T-CellReceptors, Interleukin-2RNA, MessengerSirolimusT-LymphocytesTacrolimusConceptsT cell clonesClonal proliferationCell clonesIL-2 receptor signalLymphotrophic virus type ICharacterization of HTLVInfected T cell clonesHTLV-I provirusBlood of subjectsVirus type IT cell activationAbsence of mitogensIL-2-mediated signalingIL-2-independent growthSite of actionMononuclear cellsIL-2Polymerase chain reactionT cellsExogenous growth factorsPeriodic restimulationFK-506Cell activationHTLVP55 chainT cell receptor V alpha-V beta repertoire and cytokine gene expression in active multiple sclerosis lesions.
Wucherpfennig KW, Newcombe J, Li H, Keddy C, Cuzner ML, Hafler DA. T cell receptor V alpha-V beta repertoire and cytokine gene expression in active multiple sclerosis lesions. Journal Of Experimental Medicine 1992, 175: 993-1002. PMID: 1348083, PMCID: PMC2119186, DOI: 10.1084/jem.175.4.993.Peer-Reviewed Original ResearchMeSH KeywordsAcute DiseaseAntigens, Differentiation, T-LymphocyteBase SequenceCD2 AntigensChronic DiseaseClone CellsCytokinesGene ExpressionHumansInterleukin-1Interleukin-2Interleukin-4Molecular Sequence DataMultiple SclerosisOligodeoxyribonucleotidesPolymerase Chain ReactionReceptors, Antigen, T-Cell, alpha-betaReceptors, ImmunologicRNA, MessengerConceptsTCR V alphaTCR repertoireBeta repertoireMultiple sclerosisV alphaActive lesionsMS plaquesT cellsAlpha/beta T cellsActive multiple sclerosis lesionsMS plaque tissueCentral nervous system tissueT cell recruitmentBeta T cellsActive MS plaquesChronic inflammatory diseaseIL-4 mRNAT cell expansionIL-1 mRNATCR V gene segmentsCentral nervous systemCases of subacuteNervous system tissueSites of inflammationTCR V genes
1991
Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease.
Brod SA, Benjamin D, Hafler DA. Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease. The Journal Of Immunology 1991, 147: 810-5. PMID: 1907306, DOI: 10.4049/jimmunol.147.3.810.Peer-Reviewed Original ResearchConceptsPeripheral bloodCSF of subjectsIL-5 mRNAT cell clonesIFN-gamma mRNAIL-4Inflammatory diseasesIFN-gammaIL-2Systemic inflammationT cellsTh1 T cell clonesTh2-type T cellsT cell cytokine profilesIL-2/ILDistinct T cell populationsCell clonesT cell populationsT cell expressionType T cellsTNF-alpha mRNAHuman inflammatory diseasesIL-2 mRNACytokine profileImmune compartmentInterleukin-1 corrects the defective autologous mixed lymphocyte response in multiple sclerosis
Hafler D, Chofflon M, Kurt-Jones E, Weiner H. Interleukin-1 corrects the defective autologous mixed lymphocyte response in multiple sclerosis. Clinical Immunology 1991, 58: 115-125. PMID: 1670583, DOI: 10.1016/0090-1229(91)90153-2.Peer-Reviewed Original ResearchConceptsAutologous mixed lymphocyte reactionMultiple sclerosisWhole T cellsMS patientsT cellsImmune defectsChronic progressive multiple sclerosisNon-T cell populationsAutologous mixed lymphocyte responseProgressive multiple sclerosisMixed lymphocyte responseMixed lymphocyte reactionResponse of CD4T cell populationsSex-matched controlsT cell regulationIL-1 secretionCell populationsLymphokine IFN-gammaImmunoregulatory defectsLymphocyte responsesRIL-2Lymphocyte reactionMS subjectsAutoimmune diseases