2014
Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms
Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C, Wu C, Baloglu E, Schmidt D, Ramesh R, Lobera M, Sundrud MS, Tsai PY, Xiang Z, Wang J, Xu Y, Lin X, Kretschmer K, Rahl PB, Young RA, Zhong Z, Hafler DA, Regev A, Ghosh S, Marson A, Kuchroo VK. Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms. Immunity 2014, 40: 477-489. PMID: 24745332, PMCID: PMC4066874, DOI: 10.1016/j.immuni.2014.04.004.Peer-Reviewed Original ResearchMeSH KeywordsAndrostenolsAnimalsBenzeneacetamidesBenzhydryl CompoundsCell DifferentiationCell Line, TumorCell LineageCytokinesDigoxinEncephalomyelitis, Autoimmune, ExperimentalGene Regulatory NetworksHeterocyclic Compounds, 4 or More RingsHumansMiceMice, Inbred C57BLMice, KnockoutMultiple SclerosisMyelin-Oligodendrocyte GlycoproteinNuclear Receptor Subfamily 1, Group F, Member 3Peptide FragmentsProtein BindingStructure-Activity RelationshipSystems BiologyT-Lymphocyte SubsetsTh17 CellsTranscription, GeneticTranscriptional ActivationConceptsTranscriptional networksSignature genesCis-regulatory sitesStrong transcriptional effectsInterconnected regulatory networkCell signature genesSystem-scale analysisTranscriptional regulationDirect repressorTarget lociTranscriptome sequencingRegulatory networksDNA bindingTranscriptional effectsCell lineagesCell differentiationT-cell lineageDirect activatorDivergent mechanismsT cell differentiationSpecific inhibitorDistinct mechanismsPotential therapeutic compoundsGenesRetinoid-related orphan receptor gamma t
2013
The CD226/CD155 Interaction Regulates the Proinflammatory (Th1/Th17)/Anti-Inflammatory (Th2) Balance in Humans
Lozano E, Joller N, Cao Y, Kuchroo VK, Hafler DA. The CD226/CD155 Interaction Regulates the Proinflammatory (Th1/Th17)/Anti-Inflammatory (Th2) Balance in Humans. The Journal Of Immunology 2013, 191: 3673-3680. PMID: 23980210, PMCID: PMC3819731, DOI: 10.4049/jimmunol.1300945.Peer-Reviewed Original ResearchConceptsNaive T cellsT cellsInflammatory balanceIL-13IL-17-producing cellsRole of CD226IL-17 productionIL-17 secretionHuman autoimmune diseasesIFN-γ productionIL-13 secretionIFN-γ expressionProduction of IFNSTAT-6 phosphorylationT cell activationHuman T cellsLigand CD155Th17 cellsIL-17Autoimmune diseasesIL-4T-betTh1 differentiationTh17 conditionsTherapeutic approaches
2011
Increased Frequencies of Myelin Oligodendrocyte Glycoprotein/MHC Class II-Binding CD4 Cells in Patients with Multiple Sclerosis
Raddassi K, Kent SC, Yang J, Bourcier K, Bradshaw EM, Seyfert-Margolis V, Nepom GT, Kwok WW, Hafler DA. Increased Frequencies of Myelin Oligodendrocyte Glycoprotein/MHC Class II-Binding CD4 Cells in Patients with Multiple Sclerosis. The Journal Of Immunology 2011, 187: 1039-1046. PMID: 21653833, PMCID: PMC3131477, DOI: 10.4049/jimmunol.1001543.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAmino Acid SubstitutionCD4 Lymphocyte CountCD4-Positive T-LymphocytesCell CommunicationCell Line, TransformedCells, CulturedEpitopes, T-LymphocyteFemaleGene FrequencyHLA-DR AntigensHLA-DRB1 ChainsHumansImmunophenotypingMaleMiddle AgedMultiple SclerosisMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinPeptide FragmentsProtein BindingProtein MultimerizationConceptsMyelin-reactive T cellsMultiple sclerosisT cell clonesT cellsHealthy controlsMOG-reactive T cellsAutoantigen-specific T cellsCell clonesStimulation of PMBCsClass II tetramersPathogenic immune cellsReactive T cellsSpecific T cellsMyelin oligodendrocyte glycoproteinHLA class IIBlood of subjectsT-cell cloning techniqueMOG peptidesShort-term cultureCD4 cellsMS subjectsAutoimmune diseasesPeripheral bloodControl subjectsOligodendrocyte glycoprotein
2007
Multispecific responses by T cells expanded by endogenous self‐peptide/MHC complexes
Cai G, Hafler DA. Multispecific responses by T cells expanded by endogenous self‐peptide/MHC complexes. European Journal Of Immunology 2007, 37: 602-612. PMID: 17304631, DOI: 10.1002/eji.200636787.Peer-Reviewed Original ResearchConceptsT cellsHuman T cell responsesSelf-peptide/MHCSelf-peptide/MHC complexesEndogenous self-antigenPercentage of CD4Pathological immune responsesT cell responsesAntigen-presenting cellsT cell clonesCell cycleMultispecific responseMHC determinantsSelf antigensAntigen stimulationHealthy subjectsImmune responseAntigen reactivityCD4Cell responsesMultiple antigensCD28 costimulationMHC complexesCell clonesTCRbeta chain
2003
Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27 kip1 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity*
Slavik JM, Lim DG, Burakoff SJ, Hafler DA. Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27 kip1 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity*. Journal Of Biological Chemistry 2003, 279: 910-919. PMID: 14573608, DOI: 10.1074/jbc.m209733200.Peer-Reviewed Original ResearchMeSH KeywordsAnnexin A5Antibiotics, AntineoplasticBcl-X ProteinCD28 AntigensCD3 ComplexCD8-Positive T-LymphocytesCell Cycle ProteinsCell DivisionColoring AgentsCyclin DCyclin-Dependent Kinase Inhibitor p27CyclinsDose-Response Relationship, DrugDown-RegulationEnzyme InhibitorsEstersFluoresceinsHumansKineticsLymphocytesPhosphatidylinositol 3-KinasesProtein BindingProto-Oncogene Proteins c-bcl-2Signal TransductionSirolimusT-LymphocytesTime FactorsTumor Suppressor ProteinsConceptsInhibitor of phosphoinositideT cell receptorMammalian cell typesCell receptorBcl-xL inductionAction of rapamycinBcl-xL expressionT cellsHuman cellsCell survivalP27 Kip1Resistant proliferationCell typesPhosphoinositideHuman CD8RapamycinCellular proliferationEffect of rapamycinMicrobial infectionsCell populationsHigh-affinity T-cell receptorsSelective immunosuppressive effectT Cells CorrelateT cell populationsProliferationMyelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions
O'Connor KC, Chitnis T, Griffin DE, Piyasirisilp S, Bar-Or A, Khoury S, Wucherpfennig KW, Hafler DA. Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. Journal Of Neuroimmunology 2003, 136: 140-148. PMID: 12620653, DOI: 10.1016/s0165-5728(03)00002-x.Peer-Reviewed Original ResearchConceptsMyelin basic proteinMultiple sclerosisCerebrospinal fluidSoluble myelin basic proteinSemple rabies vaccinePresence of autoantibodiesMultiple sclerosis patientsSera of patientsFraction of patientsAnti-MBP antibodiesHigh-affinity autoantibodiesBasic proteinMBP autoantibodiesRelevant autoantibodiesMS patientsSclerosis patientsAutoimmune diseasesHumoral responseRabies vaccineAutoantibodiesPatientsImmunodominant antigensSerumDiseaseSolid-phase assays
1997
Expression of a hypoglycosylated form of CD86 (B7-2) on human T cells with altered binding properties to CD28 and CTLA-4.
Höllsberg P, Scholz C, Anderson DE, Greenfield EA, Kuchroo VK, Freeman GJ, Hafler DA. Expression of a hypoglycosylated form of CD86 (B7-2) on human T cells with altered binding properties to CD28 and CTLA-4. The Journal Of Immunology 1997, 159: 4799-805. PMID: 9366404, DOI: 10.4049/jimmunol.159.10.4799.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAnimalsAntibodies, MonoclonalAntigens, CDAntigens, DifferentiationB7-2 AntigenCD28 AntigensCD3 ComplexCD4-Positive T-LymphocytesCell Line, TransformedCHO CellsClone CellsCricetinaeCTLA-4 AntigenGlycosylationHumansImmunoconjugatesLymphocyte ActivationMembrane GlycoproteinsProtein BindingT-Lymphocyte SubsetsConceptsPost-translational modificationsCell type-specific post-translational modificationsHuman T cellsDifferent cell typesMajor costimulatory signalChinese hamster ovary cellsHamster ovary cellsCell clonesFusion proteinCostimulatory signalsCell typesT cell activationFunctional significanceOvary cellsBiochemical analysisSurface membraneCostimulatory functionDetectable bindingExpressionT cellsClonesCell activationCTLA-4-Ig fusion proteinCellsCell expressionB7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors.
Greenfield EA, Howard E, Paradis T, Nguyen K, Benazzo F, McLean P, Höllsberg P, Davis G, Hafler DA, Sharpe AH, Freeman GJ, Kuchroo VK. B7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors. The Journal Of Immunology 1997, 158: 2025-34. PMID: 9036945, DOI: 10.4049/jimmunol.158.5.2025.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAnimalsAntigens, CDAntigens, DifferentiationB7-2 AntigenCD28 AntigensCell DivisionCTLA-4 AntigenFemaleImmunoconjugatesLymphocyte ActivationMembrane GlycoproteinsMiceMice, Inbred BALB CMice, Inbred C57BLProtein BindingT-LymphocytesThymomaThymus NeoplasmsTransfectionTumor Cells, Cultured
1995
Structure of human T-cell receptors specific for an immunodominant myelin basic protein peptide: positioning of T-cell receptors on HLA-DR2/peptide complexes.
Wucherpfennig KW, Hafler DA, Strominger JL. Structure of human T-cell receptors specific for an immunodominant myelin basic protein peptide: positioning of T-cell receptors on HLA-DR2/peptide complexes. Proceedings Of The National Academy Of Sciences Of The United States Of America 1995, 92: 8896-8900. PMID: 7568039, PMCID: PMC41074, DOI: 10.1073/pnas.92.19.8896.Peer-Reviewed Original Research