2016
The Link Between CD6 and Autoimmunity: Genetic and Cellular Associations.
Kofler DM, Farkas A, von Bergwelt-Baildon M, Hafler DA. The Link Between CD6 and Autoimmunity: Genetic and Cellular Associations. Current Drug Targets 2016, 17: 651-65. PMID: 26844569, DOI: 10.2174/1389450117666160201105934.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteArthritis, RheumatoidAutoimmunityCD4-Positive T-LymphocytesCell Adhesion Molecules, NeuronalClinical Trials as TopicDisease Models, AnimalFetal ProteinsGenetic Predisposition to DiseaseHumansMultiple SclerosisPolymorphism, Single NucleotideConceptsMultiple sclerosisRheumatoid arthritisCentral nervous systemNervous systemSingle nucleotide polymorphismsDevelopment of MSTreatment of RARole of CD6T cell traffickingT cell functionGenetic risk factorsEndothelial cell barrierCD6 geneClinical responseGenetic associationClinical featuresAutoimmune diseasesSynovial cellsRisk factorsTumor necrosisSynovial fibroblastsPossible common mechanismT cellsT lymphocytesLeukocyte trafficking
2014
Enhanced suppressor function of TIM‐3+FoxP3+ regulatory T cells
Gautron A, Dominguez-Villar M, de Marcken M, Hafler DA. Enhanced suppressor function of TIM‐3+FoxP3+ regulatory T cells. European Journal Of Immunology 2014, 44: 2703-2711. PMID: 24838857, PMCID: PMC4165702, DOI: 10.1002/eji.201344392.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDCell DifferentiationCTLA-4 AntigenFemaleForkhead Transcription FactorsGene Expression RegulationGranzymesHepatitis A Virus Cellular Receptor 2HumansInterleukin 1 Receptor Antagonist ProteinInterleukin-10InterleukinsLymphocyte Activation Gene 3 ProteinMaleMembrane ProteinsMiceMinor Histocompatibility AntigensReceptors, CCR6STAT3 Transcription FactorTh17 CellsT-Lymphocytes, RegulatoryConceptsTim-3 expressionRegulatory T cellsTreg cellsTim-3T cellsNatural regulatory T cellsMucin domain 3Number of TIMTh17 cell responseEffector T cellsT cell suppressionHuman Treg cellsT-cell immunoglobulinAnti-CD28 stimulationT cell differentiationSTAT-3 expressionPathogenic Th1Th17 cellsTc1 cellsImmune toleranceTh1 cellsLevel of expressionReduced gene expressionGene expressionSuppressor function
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
Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci
De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, Piccio L, Raychaudhuri S, Tran D, Aubin C, Briskin R, Romano S, Baranzini S, McCauley J, Pericak-Vance M, Haines J, Gibson R, Naeglin Y, Uitdehaag B, Matthews P, Kappos L, Polman C, McArdle W, Strachan D, Evans D, Cross A, Daly M, Compston A, Sawcer S, Weiner H, Hauser S, Hafler D, Oksenberg J. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genetics 2009, 41: 776-782. PMID: 19525953, PMCID: PMC2757648, DOI: 10.1038/ng.401.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
TIMs: central regulators of immune responses
Hafler DA, Kuchroo V. TIMs: central regulators of immune responses. Journal Of Experimental Medicine 2008, 205: 2699-2701. PMID: 19015312, PMCID: PMC2585854, DOI: 10.1084/jem.20082429.Peer-Reviewed Original ResearchConceptsExhausted T cellsT cell exhaustionHIV infectionPD-1T cellsCell exhaustionMucin domain-containing protein 3Chronic HIV infectionChronic viral infectionsHuman HIV infectionT cell responsesChronic viral diseasesT-cell immunoglobulinDomain-containing protein 3Novel therapeutic targetTim-3Opportunistic infectionsCell immunoglobulinImmune responseTherapeutic targetViral infectionCell responsesProtein 3InfectionViral diseases
2007
Allelic variant in CTLA4 alters T cell phosphorylation patterns
Maier LM, Anderson DE, De Jager PL, Wicker LS, Hafler DA. Allelic variant in CTLA4 alters T cell phosphorylation patterns. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 18607-18612. PMID: 18000051, PMCID: PMC2141824, DOI: 10.1073/pnas.0706409104.Peer-Reviewed Original ResearchConceptsT cell antigen receptorAllelic variationMemory T cellsAutoimmune diseasesCell antigen receptorT cell signalingT cellsFunctional effectsDisease susceptibility allelesCell signalingPhosphorylation patternPhosphorylation levelsSusceptibility variantsTCR stimulationAllelic variantsHuman immune cellsAntigen receptorGenesImmune cellsHealthy individualsCTLA4 geneCellsSpecific mAbsCTLA4Disease
2005
Functional 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
PD-1 ligands, negative regulators for activation of naïve, memory, and recently activated human CD4+ T cells
Cai G, Karni A, Oliveira EM, Weiner HL, Hafler DA, Freeman GJ. PD-1 ligands, negative regulators for activation of naïve, memory, and recently activated human CD4+ T cells. Cellular Immunology 2004, 230: 89-98. PMID: 15598424, DOI: 10.1016/j.cellimm.2004.09.004.Peer-Reviewed Original ResearchConceptsPD-1 ligand blockadeT cellsPD-L1Myelin basic proteinPD-L2Human CD4Ex vivo dendritic cellsVivo dendritic cellsPD-1 ligandsPD-1 pathwayPrimary responseActivation of naïveNaive T cellsPD-1Dendritic cellsCytokine productionNormal donorsIFN-gammaSecondary responseCD4BlockadeHigh expressionNegative regulatory pathwaysInduced activationBasic proteinAn 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 linkageHuman CD4+CD25+ regulatory T cells
Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells. Seminars In Immunology 2004, 16: 89-98. PMID: 15036232, DOI: 10.1016/j.smim.2003.12.005.Peer-Reviewed Original ResearchConceptsRegulatory T cellsT reg cellsT cellsT reg populationT cell subsetsT-reg functionHuman peripheral bloodIL-10Lymph nodesPeripheral bloodCell subsetsFunctional outcomeCord bloodTCR stimuliRapid effectsCellular compositionTCR signalsPotential involvementActivation stateStrong stimulationMiceBloodDisparate findingsCellsCulture conditions
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 levelsCD25CD45ROCTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls
Oliveira EM, Bar-Or A, Waliszewska AI, Cai G, Anderson DE, Krieger JI, Hafler DA. CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls. Journal Of Autoimmunity 2003, 20: 71-81. PMID: 12604314, DOI: 10.1016/s0896-8411(02)00106-3.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsMyelin basic proteinHealthy controlsMyelin basic protein-reactive T cellsMBP-reactive T cellsPathogenesis of MSPeripheral blood mononuclear cellsCTLA-4 blockadeReactive T cellsBlood mononuclear cellsCo-stimulatory pathwaysNaïve T cellsCo-stimulatory signalsCentral nervous systemCTLA-4 engagementCytokine responsesAutoimmune responseMononuclear cellsInflammatory diseasesB7-CD28Proliferative responseNervous systemPatientsMyelin sheathCTLA4 is associated with susceptibility to multiple sclerosis
Kantarci OH, Hebrink DD, Achenbach SJ, Atkinson EJ, Waliszewska A, Buckle G, McMurray CT, de Andrade M, Hafler DA, Weinshenker BG. CTLA4 is associated with susceptibility to multiple sclerosis. Journal Of Neuroimmunology 2003, 134: 133-141. PMID: 12507781, DOI: 10.1016/s0165-5728(02)00395-8.Peer-Reviewed Original ResearchAbataceptAge of OnsetAlternative SplicingAntigens, CDAntigens, DifferentiationBostonCTLA-4 AntigenDisease ProgressionDNA Mutational AnalysisExonsFemaleGenetic LinkageGenetic Predisposition to DiseaseGenetic TestingGenetic VariationGenotypeHaplotypesHumansImmunoconjugatesMaleMicrosatellite RepeatsMinnesotaMultiple SclerosisPolymorphism, Genetic
2002
Strength of prior stimuli determines the magnitude of secondary responsiveness in CD8+ T cells
Lim DG, Höllsberg P, Hafler DA. Strength of prior stimuli determines the magnitude of secondary responsiveness in CD8+ T cells. Cellular Immunology 2002, 217: 36-46. PMID: 12425999, DOI: 10.1016/s0008-8749(02)00511-7.Peer-Reviewed Original ResearchConceptsT cellsSecondary responsivenessCostimulatory moleculesInduction of CD8Magnitude of CD8T cell responsesT cell anergyCell anergyCD8Prior stimulusSecondary stimulationPrimary stimulationCell responsesCellular mechanismsFollowing activationPeptide ligandsActivation thresholdStimulationCellsResponsivenessHigh levelsCD4AnergyStimuliStrength of signalGAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes
Viglietta V, Kent SC, Orban T, Hafler DA. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. Journal Of Clinical Investigation 2002, 109: 895-903. PMID: 11927616, PMCID: PMC150925, DOI: 10.1172/jci14114.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAdultAntigens, CDAntigens, DifferentiationAutoimmunityB7-1 AntigenB7-2 AntigenCD28 AntigensCell DivisionCTLA-4 AntigenDiabetes Mellitus, Type 1FemaleGlutamate DecarboxylaseHumansImmunoconjugatesInterferon-gammaInterleukin-13IsoenzymesMaleMembrane GlycoproteinsSignal TransductionT-LymphocytesConceptsGAD65-reactive T cellsType 1 diabetesAutoreactive T cellsT cellsB7-1New-onset type 1 diabetesPancreatic islet cell antigensInsulin-dependent type 1 diabetesGlutamic acid decarboxylase 65B7-2 engagementType 1A diabetesMemory T cellsStimulation ex vivoIslet cell antigensB7-2 moleculesT cell proliferationB7-1 costimulationAutoimmune diseasesCTLA-4Healthy controlsPathogenic roleSelective blockadeCytokine secretionHuman diabetesT lymphocytes
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-2
2000
A novel population of B7‐1+ T cells producing intracellular IL‐4 is decreased in patients with multiple sclerosis
Kipp B, Bar‐Or A, Gausling R, Oliveira E, Fruhan S, Stuart W, Hafler D. A novel population of B7‐1+ T cells producing intracellular IL‐4 is decreased in patients with multiple sclerosis. European Journal Of Immunology 2000, 30: 2092-2100. PMID: 10940899, DOI: 10.1002/1521-4141(200007)30:7<2092::aid-immu2092>3.0.co;2-7.Peer-Reviewed Original ResearchConceptsT cell receptorIntracellular IL-4Multiple sclerosisT cellsB7-1IL-4Autoimmune diseasesTNF-alphaIFN-gammaIL-4-producing T cellsLittle IL-4Immunoregulatory T cellsIL-4 productionIntracellular IFN-gammaT cell populationsLittle IFN-gammaNovel populationDiverse TCR repertoireMHC class IIHuman T cellsShort-term cultureCell surface moleculesTCR repertoireNormal subjectsPatientsParadoxical inhibition of T-cell function in response to CTLA-4 blockade; heterogeneity within the human T-cell population
Anderson D, Bieganowska K, Bar-Or A, Oliveira E, Carreno B, Collins M, Hafler D. Paradoxical inhibition of T-cell function in response to CTLA-4 blockade; heterogeneity within the human T-cell population. Nature Medicine 2000, 6: 211-214. PMID: 10655112, DOI: 10.1038/72323.Peer-Reviewed Original ResearchConceptsCTLA-4 blockadeT cell populationsCTLA-4T cellsMonoclonal antibodiesB7-1B7-2Immune responseCytotoxic T-lymphocyte antigen-4Whole T cell populationsT-lymphocyte antigen-4Antigen-specific T cellsT cell activation stateHuman T cell populationsT cell functionT cell receptor signalsCo-stimulatory signalsDifferent T cellsT cell stimulationEffect of B7T cell activationActivation stateT cell receptorHuman T cellsFab fragments