2023
Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity
Shinoda K, Li R, Rezk A, Mexhitaj I, Patterson K, Kakara M, Zuroff L, Bennett J, von Büdingen H, Carruthers R, Edwards K, Fallis R, Giacomini P, Greenberg B, Hafler D, Ionete C, Kaunzner U, Lock C, Longbrake E, Pardo G, Piehl F, Weber M, Ziemssen T, Jacobs D, Gelfand J, Cross A, Cameron B, Musch B, Winger R, Jia X, Harp C, Herman A, Bar-Or A. Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2207291120. PMID: 36634138, PMCID: PMC9934304, DOI: 10.1073/pnas.2207291120.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CD20CD8-Positive T-LymphocytesFlow CytometryHumansLeukocytes, MononuclearMultiple SclerosisRecurrenceConceptsEarly disease activityDisease activityCD8 T cellsT cellsCD20 therapyPeripheral blood mononuclear cellsCellular immune profilesNew disease activityMS disease activityT cell poolMultiple sclerosis patientsAnti-inflammatory profileBlood mononuclear cellsTreatment-associated changesMultiparametric flow cytometryCentral nervous systemFurther dosingRepeat infusionsImmune profileMS patientsSclerosis patientsValidation cohortMononuclear cellsRelapse developmentImmune cascade
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
2014
Joint Modeling and Registration of Cell Populations in Cohorts of High-Dimensional Flow Cytometric Data
Pyne S, Lee SX, Wang K, Irish J, Tamayo P, Nazaire MD, Duong T, Ng SK, Hafler D, Levy R, Nolan GP, Mesirov J, McLachlan GJ. Joint Modeling and Registration of Cell Populations in Cohorts of High-Dimensional Flow Cytometric Data. PLOS ONE 2014, 9: e100334. PMID: 24983991, PMCID: PMC4077578, DOI: 10.1371/journal.pone.0100334.Peer-Reviewed Original ResearchMeSH KeywordsAlgorithmsCluster AnalysisComputational BiologyComputer SimulationFlow CytometryHumansSoftwareConceptsMultivariate probability distributionProbability distributionMultivariate responseJCM modelMultiple experimental conditionsJoint modelingJoint clusteringSimultaneous modelingComputational methodsRegistration of populationTypical experimentModelingNew samplesModelJCMFlow cytometric dataMultiparametric cytometrySystem-level variationApplications
2013
Specific peripheral B cell tolerance defects in patients with multiple sclerosis
Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, Herold KC, Hafler DA, O’Connor K, Meffre E. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. Journal Of Clinical Investigation 2013, 123: 2737-2741. PMID: 23676463, PMCID: PMC3668812, DOI: 10.1172/jci68775.Peer-Reviewed Original ResearchConceptsB cell tolerance checkpointsB cell tolerance defectsMultiple sclerosisRheumatoid arthritisTolerance checkpointsB cellsPeripheral B cell tolerance checkpointsTolerance defectsAutoreactive B cell clonesMature naive B cellsType 1 diabetesAutoreactive B cellsB cell toleranceCentral nervous systemNaive B cellsB cell clonesB cell selectionEarly B cell developmentIPEX patientsMost patientsTreg functionHomeostatic proliferationAutoimmune diseasesPatientsHealthy individuals
2011
The CD6 Multiple Sclerosis Susceptibility Allele Is Associated with Alterations in CD4+ T Cell Proliferation
Kofler DM, Severson CA, Mousissian N, De Jager PL, Hafler DA. The CD6 Multiple Sclerosis Susceptibility Allele Is Associated with Alterations in CD4+ T Cell Proliferation. The Journal Of Immunology 2011, 187: 3286-3291. PMID: 21849685, DOI: 10.4049/jimmunol.1100626.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAntigens, CDAntigens, Differentiation, T-LymphocyteCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell ProliferationCell SeparationCells, CulturedFemaleFlow CytometryGenetic Predisposition to DiseaseGenotypeHumansMaleMultiple SclerosisPhenotypeReverse Transcriptase Polymerase Chain ReactionRisk FactorsRNA, Small InterferingConceptsGenome-wide association studiesAssociation studiesAllelic variantsNew susceptibility lociSusceptibility allelesRisk allelesProliferation defectExon 5Risk-associated allelesSingle nucleotide polymorphismsExtracellular binding sitesCD6 geneSusceptibility lociLinkage disequilibriumMS risk alleleSelective knockdownT cell activationNucleotide polymorphismsAltered proliferationCell proliferationGenetic associationAllelesLong-term activationBinding sitesMS susceptibility alleles
2009
Automated high-dimensional flow cytometric data analysis
Pyne S, Hu X, Wang K, Rossin E, Lin TI, Maier LM, Baecher-Allan C, McLachlan GJ, Tamayo P, Hafler DA, De Jager PL, Mesirov JP. Automated high-dimensional flow cytometric data analysis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 8519-8524. PMID: 19443687, PMCID: PMC2682540, DOI: 10.1073/pnas.0903028106.Peer-Reviewed Original ResearchIL-17–producing human peripheral regulatory T cells retain suppressive function
Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, Hafler DA. IL-17–producing human peripheral regulatory T cells retain suppressive function. Blood 2009, 113: 4240-4249. PMID: 19171879, PMCID: PMC2676084, DOI: 10.1182/blood-2008-10-183251.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CDEnzyme-Linked Immunosorbent AssayFlow CytometryForkhead Transcription FactorsHLA-DR AntigensHumansImmune ToleranceInterleukin-17Interleukin-1betaInterleukin-6Lymphocyte ActivationReverse Transcriptase Polymerase Chain ReactionT-LymphocytesT-Lymphocytes, RegulatoryTransforming Growth Factor betaConceptsRegulatory T cellsIL-17Suppressive functionTreg clonesT cellsPeripheral regulatory T cellsProinflammatory cytokines IL-1betaSustained Foxp3 expressionIL-17 productionIL-17 secretionCytokines IL-1betaAutoimmune pathogenesisEffector cellsInterleukin-17Foxp3 expressionHuman TregsInflammatory milieuIL-6IL-1betaInflammatory conditionsImmune functionSuppressive activityTregsCellsRecent studies
2008
Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells
De Jager PL, Rossin E, Pyne S, Tamayo P, Ottoboni L, Viglietta V, Weiner M, Soler D, Izmailova E, Faron-Yowe L, O’Brien C, Freeman S, Granados S, Parker A, Roubenoff R, Mesirov JP, Khoury SJ, Hafler DA, Weiner HL. Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells. Brain 2008, 131: 1701-1711. PMID: 18567923, PMCID: PMC2730047, DOI: 10.1093/brain/awn118.Peer-Reviewed Original ResearchConceptsRelapsing-remitting MSImmunological profileRRMS subjectsPeripheral bloodUntreated subjectsNatural killer cell profileComprehensive Longitudinal InvestigationAbsence of treatmentCell surface markersCIS subjectsDemyelinating diseaseDemyelination syndromeWomen's HospitalHealthy controlsCytometric profilingCell profilesMonoclonal antibodiesExtension phaseFresh bloodBiomarker discovery effortsDistinct subsetsBloodCell populationsGating strategyHospital
2006
Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis
Astier AL, Meiffren G, Freeman S, Hafler DA. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. Journal Of Clinical Investigation 2006, 116: 3252-3257. PMID: 17099776, PMCID: PMC1635165, DOI: 10.1172/jci29251.Peer-Reviewed Original ResearchConceptsIL-10 secretionTr1 regulatory T cellsRegulatory T cellsHuman autoimmune diseasesMultiple sclerosisT cellsAutoimmune diseasesTr1 cellsIL-10Antiinflammatory cytokine IL-10Cytokine IL-10IFN-gamma secretionT cell functionT cell activationHuman T cellsTreg defectsTreg phenotypeTreg functionCostimulatory moleculesHealthy subjectsMurine modelCD46 costimulationCell activationCD28 costimulationPatientsThe Purification and Functional Analysis of Human CD4+CD25high Regulatory T Cells
Baecher-Allan C, Hafler DA. The Purification and Functional Analysis of Human CD4+CD25high Regulatory T Cells. Current Protocols In Immunology 2006, 72: 7.4b.1-7.4b.12. PMID: 18432975, DOI: 10.1002/0471142735.im0704bs72.Peer-Reviewed Original ResearchMeSH KeywordsFlow CytometryHumansImmunomagnetic SeparationInterleukin-2 Receptor alpha SubunitT-Lymphocytes, RegulatoryConceptsRegulatory T cellsCD4 T cellsT cellsHuman regulatory T cellsHuman CD4 T cellsLevels of CD25Suppressive featuresCD25Coculture assaysVitro proliferationHigh expressionVivo developmentEndogenous expressionSuch cellsCellsSmall percentageMouse cellsHigh levelsAutoimmunityHumansExpressionMiceBlood
2005
Letter to the Editor
Baecher-Allan CM, Hafler DA. Letter to the Editor. Clinical Immunology 2005, 117: 192. PMID: 16214081, DOI: 10.1016/j.clim.2005.08.008.Peer-Reviewed Original ResearchFunctional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells
Baecher-Allan C, Wolf E, Hafler DA. Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells. Clinical Immunology 2005, 115: 10-18. PMID: 15870015, DOI: 10.1016/j.clim.2005.02.018.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CDAntigens, Differentiation, B-LymphocyteCD4-Positive T-LymphocytesCD58 AntigensCoculture TechniquesEnzyme-Linked Immunosorbent AssayFlow CytometryHumansImmunoglobulin GImmunophenotypingLeukocyte Common AntigensL-SelectinReceptors, Interleukin-2Receptors, TransferrinT-Lymphocyte SubsetsConceptsCD4 T cellsT cellsTreg cellsRegulatory cellsTotal CD4 T cellsHuman regulatory cellsRegulatory T cellsAutoimmune disease modelsImportance of CD4Regulatory populationImmune homeostasisCD25Suppressive activityCD4Human regulatorySpecific subpopulationsDisease modelsSignificant proportionMiceVivoMurine cellsPotential heterogeneityFuture studiesCellsHuman diseases
2004
An Autoimmune Disease-Associated CTLA-4 Splice Variant Lacking the B7 Binding Domain Signals Negatively in T Cells
Vijayakrishnan L, Slavik JM, Illés Z, Greenwald RJ, Rainbow D, Greve B, Peterson LB, Hafler DA, Freeman GJ, Sharpe AH, Wicker LS, Kuchroo VK. An Autoimmune Disease-Associated CTLA-4 Splice Variant Lacking the B7 Binding Domain Signals Negatively in T Cells. Immunity 2004, 20: 563-575. PMID: 15142525, DOI: 10.1016/s1074-7613(04)00110-4.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsAntigens, CDAntigens, DifferentiationAutoimmune DiseasesB7-1 AntigenBlotting, WesternCloning, MolecularCTLA-4 AntigenFemaleFlow CytometryHumansMembrane ProteinsMiceMice, Inbred NODMolecular Sequence DataReceptors, Antigen, T-CellReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSignal TransductionT-LymphocytesConceptsCytotoxic T-lymphocyte-associated antigen 4T cell responsesT cellsNOD miceAutoimmune diseasesT cell-mediated autoimmune diseaseT-lymphocyte-associated antigen 4Cell responsesCell-mediated autoimmune diseaseSusceptible NOD miceRegulatory T cellsNOD congenic miceCTLA-4 locusAntigen-4B7-1B7-2Primary T cellsCongenic miceSplice variantsMiceNegative signalingMYPPPY motifDiseaseType IGenetic linkage
2003
CD4+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 levelsCD25CD45ROActivated CD8+ T cells in secondary progressive MS secrete lymphotoxin
Buckle GJ, Höllsberg P, Hafler DA. Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin. Neurology 2003, 60: 702-705. PMID: 12601116, DOI: 10.1212/01.wnl.0000048204.89346.30.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodiesCD3 ComplexCD8-Positive T-LymphocytesCell DivisionCell SeparationCells, CulturedCytokinesFemaleFlow CytometryGene FrequencyHumansLymphotoxin-alphaMaleMiddle AgedMultiple Sclerosis, Chronic ProgressiveMultiple Sclerosis, Relapsing-RemittingPolymorphism, Single NucleotideReference ValuesConceptsT cellsNormal controlsSecondary progressive MSCytokine secretion profileFunctional activation statesLymphotoxin secretionProgressive MSActivated CD8Cytokine secretionSecretion profileCytokine genesCD8SecretionSignificant differencesPatientsSignificant increaseActivation stateSingle nucleotide polymorphism analysisPolymorphism analysisNucleotide polymorphism analysisCells
2001
In vitro evidence that immunuaffinity-purified MOG contains immunogenic quantities of contaminating mouse IgG; techniques for producing Ig-free MOG
Ohashi T, Yukitake M, Slavin A, Krieger J, Hafler D. In vitro evidence that immunuaffinity-purified MOG contains immunogenic quantities of contaminating mouse IgG; techniques for producing Ig-free MOG. Journal Of Neuroimmunology 2001, 118: 194-202. PMID: 11498254, DOI: 10.1016/s0165-5728(01)00321-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalAntibody SpecificityBlotting, WesternCell LineClone CellsCytokinesElectrophoresis, Polyacrylamide GelEnzyme-Linked Immunosorbent AssayFlow CytometryHumansImmunoglobulin GImmunophenotypingImmunosorbent TechniquesLymphocyte ActivationMiceMultiple SclerosisMyelin ProteinsMyelin SheathMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinSensitivity and SpecificityT-Lymphocytes
1998
Differential Display Cloning of a Novel Human Histone Deacetylase (HDAC3) cDNA from PHA-Activated Immune Cells
Dangond F, Hafler D, Tong J, Randall J, Kojima R, Utku N, Gullans S. Differential Display Cloning of a Novel Human Histone Deacetylase (HDAC3) cDNA from PHA-Activated Immune Cells. Biochemical And Biophysical Research Communications 1998, 242: 648-652. PMID: 9464271, DOI: 10.1006/bbrc.1997.8033.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBlotting, NorthernCD3 ComplexCell CycleCloning, MolecularDNAFlow CytometryGene Expression Regulation, EnzymologicGranulocyte-Macrophage Colony-Stimulating FactorHistone DeacetylasesHumansMolecular Sequence DataPhylogenyPhytohemagglutininsRNA, MessengerSequence AlignmentSequence Analysis, DNAT-LymphocytesTransfectionTumor Cells, CulturedConceptsPeripheral blood mononuclear cellsBlock T cell proliferationEffects of HDACsBlood mononuclear cellsT cell proliferationT cell clonesG2/M cell accumulationNon-immune tissuesTHP-1 cellsHDAC mRNAsPBMC levelsDifferential display cloningMononuclear cellsIL-4Immune cellsIFN-gammaAlpha CD3Histone acetyltransferasesCell accumulationHDAC3 mRNAHDAC inhibitorsHistone deacetylase assayCell clonesCell cycle progressionFunctional activity
1995
Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements.
Stinissen P, Vandevyver C, Medaer R, Vandegaer L, Nies J, Tuyls L, Hafler DA, Raus J, Zhang J. Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements. The Journal Of Immunology 1995, 154: 4883-94. PMID: 7722338, DOI: 10.4049/jimmunol.154.9.4883.Peer-Reviewed Original ResearchConceptsGamma delta T cell clonesGamma delta T cellsDelta T cellsT cell clonesGamma delta clonesMultiple sclerosisPeripheral bloodT cellsCerebrospinal fluidMS patientsOND patientsCell clonesControl subjectsNormal individualsBacterial superantigen staphylococcal enterotoxin BCentral nervous system demyelinationCSF of patientsSuperantigen staphylococcal enterotoxin BToxic shock syndrome toxin-1Nervous system demyelinationClonal originSecondary inflammatory processesV gene usageSyndrome toxin-1Staphylococcal enterotoxin B
1994
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.
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
T-cell activation by autologous human T-cell leukemia virus type I-infected T-cell clones.
Wucherpfennig KW, Höllsberg P, Richardson JH, Benjamin D, Hafler DA. T-cell activation by autologous human T-cell leukemia virus type I-infected T-cell clones. Proceedings Of The National Academy Of Sciences Of The United States Of America 1992, 89: 2110-2114. PMID: 1549569, PMCID: PMC48606, DOI: 10.1073/pnas.89.6.2110.Peer-Reviewed Original ResearchConceptsIntercellular cell adhesion moleculeBlood T cellsT cell clonesT cell activationIL-2 receptorT cellsActivated T cellsHuman T-cell leukemia virus type I (HTLV-I) carriersSuch activated T cellsHAM/TSP patientsMyelopathy/tropical spastic paraparesisClass II major histocompatibility complex moleculesHAM/TSPChronic inflammatory diseaseExogenous interleukin-2HTLV-I infectionTropical spastic paraparesisMajor histocompatibility complex moleculesHuman T-cell leukemia virus type IVirus type IHistocompatibility complex moleculesCD2/LFATSP patientsSpastic paraparesisSpontaneous proliferation