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
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
2005
Characterization of in vivo expanded OspA-specific human T-cell clones
Ausubel LJ, O'Connor KC, Baecher-Allen C, Trollmo C, Kessler B, Hekking B, Merritt D, Meyer AL, Kwok B, Ploegh H, Huber BT, Hafler DA. Characterization of in vivo expanded OspA-specific human T-cell clones. Clinical Immunology 2005, 115: 313-322. PMID: 15893699, DOI: 10.1016/j.clim.2005.02.015.Peer-Reviewed Original ResearchConceptsT cell clonesMajor histocompatibility complex class II tetramersTreatment-resistant Lyme arthritisCD4 T-cell clonesDistinct T-cell clonesT cell receptor repertoireHuman T cell clonesClass II tetramersBeta chainT cell recognitionTCR contact residuesTCR beta chainT cell receptorCell flow cytometryTCR usageImmune compartmentLyme arthritisAutoimmune diseasesMicrobial antigensT cellsOspA epitopeImmunodominant epitopesSynovial fluidReceptor repertoireReactive clonesHigh Incidence of Spontaneous Disease in an HLA-DR15 and TCR Transgenic Multiple Sclerosis Model
Ellmerich S, Mycko M, Takacs K, Waldner H, Wahid FN, Boyton RJ, King RH, Smith PA, Amor S, Herlihy AH, Hewitt RE, Jutton M, Price DA, Hafler DA, Kuchroo VK, Altmann DM. High Incidence of Spontaneous Disease in an HLA-DR15 and TCR Transgenic Multiple Sclerosis Model. The Journal Of Immunology 2005, 174: 1938-1946. PMID: 15699121, DOI: 10.4049/jimmunol.174.4.1938.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationCell MovementCentral Nervous SystemDisease Models, AnimalDisease ProgressionDNA-Binding ProteinsEpitopes, T-LymphocyteHLA-DR AntigensHLA-DR Serological SubtypesMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMultiple SclerosisMyelin Basic ProteinParalysisPeptide FragmentsReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsConceptsT cell responsesHLA-DR15Multiple sclerosisDeterminant spreadSpontaneous diseaseCell responsesCD4 T cell recognitionCNS tissue damageHuman multiple sclerosisMultiple sclerosis modelT cell reactivityExperimental allergic encephalomyelitisMyelin oligodendrocyte glycoproteinT cell recognitionMyelin basic proteinAllergic encephalomyelitisMyelin epitopesPeptide immunotherapyAxonal degenerationCell reactivityOligodendrocyte glycoproteinPathogenic roleT cellsHigh incidenceTransgenic mice
2004
Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules
Mycko MP, Waldner H, Anderson DE, Bourcier KD, Wucherpfennig KW, Kuchroo VK, Hafler DA. Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules. The Journal Of Immunology 2004, 173: 1689-1698. PMID: 15265898, DOI: 10.4049/jimmunol.173.3.1689.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsAntigen PresentationAutoantigensCD4 AntigensCross ReactionsEncephalomyelitis, Autoimmune, ExperimentalHLA-DR alpha-ChainsHLA-DR AntigensHLA-DRB1 ChainsHumansHybridomasL CellsLymphocyte ActivationMembrane ProteinsMiceMolecular Sequence DataMultiple Sclerosis, Relapsing-RemittingMyelin Basic ProteinPeptide FragmentsPhosphorylationProtein Processing, Post-TranslationalReceptors, Antigen, T-CellReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsTransfectionConceptsAutoreactive T cellsMHC class II moleculesClass II moleculesT cellsSpontaneous experimental autoimmune encephalomyelitisRelapsing-remitting multiple sclerosisDifferent MHC class II moleculesExperimental autoimmune encephalomyelitisAltered peptide ligandTh cell clonesT cell hybridomasMyelin basic proteinAutoimmune encephalomyelitisMultiple sclerosisSelf antigensCD4 coreceptorRestriction elementsHealthy individualsDiseased patientsHuman TCRPatientsTCR responsesCell clonesCell hybridomasPeptide ligands
2003
Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8+ T Cell Function
Lim DG, Slavik JM, Bourcier K, Smith KJ, Hafler DA. Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8+ T Cell Function. Journal Of Experimental Medicine 2003, 198: 99-109. PMID: 12847139, PMCID: PMC2196091, DOI: 10.1084/jem.20021796.Peer-Reviewed Original ResearchConceptsT cell functionT cell clonesCell functionReactive T cell clonesCell clonesT cell responsesDifferent T cell responsesIndividual T cell clonesHLA-A2 moleculesAltered peptide ligandHLA-A2 peptideRecognition of MHCT cell receptorMHC-peptide complexesPolymorphic amino acidsFunctional outcomeHLA-A2Peptide ligandsAgonist functionMHC moleculesCell responsesEarly intracellularLong-term expressionCell receptorAntigen recognition
2001
Molecular Mimicry in Lyme Arthritis Demonstrated at the Single Cell Level: LFA-1αL Is a Partial Agonist for Outer Surface Protein A-Reactive T Cells
Trollmo C, Meyer A, Steere A, Hafler D, Huber B. Molecular Mimicry in Lyme Arthritis Demonstrated at the Single Cell Level: LFA-1αL Is a Partial Agonist for Outer Surface Protein A-Reactive T Cells. The Journal Of Immunology 2001, 166: 5286-5291. PMID: 11290815, DOI: 10.4049/jimmunol.166.8.5286.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, SurfaceBacterial Outer Membrane ProteinsBacterial VaccinesBorrelia burgdorferi GroupClone CellsHumansHybridomasLipoproteinsLyme DiseaseLyme Disease VaccinesLymphocyte ActivationLymphocyte Function-Associated Antigen-1MiceMice, TransgenicMolecular MimicryPeptide FragmentsT-Lymphocyte SubsetsConceptsIL-13Antibiotic treatment-resistant Lyme arthritisPartial agonistTreatment-resistant Lyme arthritisChronic inflammatory joint diseaseT cell hybridsDR4 transgenic miceHuman T cell clonesClass II tetramersInflammatory joint diseaseSymptoms of arthritisT cell responsesT cell levelsEpisodes of arthritisT cell clonesSurface protein AAutoimmune mechanismsOuter surface protein ALyme arthritisJoint diseaseT cellsIFN-gammaImmunodominant epitopesCell levelTransgenic mice
2000
Examination of CD8+ T Cell Function in Humans Using MHC Class I Tetramers: Similar Cytotoxicity but Variable Proliferation and Cytokine Production Among Different Clonal CD8+ T Cells Specific to a Single Viral Epitope
Lim D, Bourcier K, Freeman G, Hafler D. Examination of CD8+ T Cell Function in Humans Using MHC Class I Tetramers: Similar Cytotoxicity but Variable Proliferation and Cytokine Production Among Different Clonal CD8+ T Cells Specific to a Single Viral Epitope. The Journal Of Immunology 2000, 165: 6214-6220. PMID: 11086055, DOI: 10.4049/jimmunol.165.11.6214.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, ViralB7-1 AntigenCD58 AntigensCD8-Positive T-LymphocytesCell Line, TransformedClone CellsCytokinesCytotoxicity, ImmunologicDose-Response Relationship, ImmunologicEpitopes, T-LymphocyteGene Products, taxGenes, T-Cell Receptor betaHLA-A2 AntigenHuman T-lymphotropic virus 1HumansLymphocyte ActivationPeptide FragmentsStaining and LabelingConceptsT cell clonesCytokine secretionT cellsEffector functionsCell clonesCostimulatory moleculesViral epitopesHuman T-cell lymphotrophic virusDifferent T cell clonesImmunodominant viral epitopesCytotoxic effector functionClonal originT cell functionSingle viral epitopeMHC class IDifferent clonal originCD2-LFA-3 interactionInduction of proliferationClonal CD8Cytokine productionPeripheral bloodCTL populationsIL-2Lymphotrophic virusProliferative responseGlatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis
Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. Journal Of Clinical Investigation 2000, 105: 967-976. PMID: 10749576, PMCID: PMC377485, DOI: 10.1172/jci8970.Peer-Reviewed Original ResearchMeSH KeywordsAdultAmino Acid SequenceCell DivisionCells, CulturedCross ReactionsEpitopes, T-LymphocyteFemaleGlatiramer AcetateHumansImmunodominant EpitopesImmunosuppressive AgentsInterferon-gammaInterleukin-5Leukocytes, MononuclearLigandsMaleMiddle AgedMolecular Sequence DataMultiple SclerosisMyelin Basic ProteinMyelin SheathPeptide FragmentsPeptidesTetanus ToxoidTh2 CellsConceptsT cell responsesMultiple sclerosisGlatiramer acetateT cellsAntigen-specific T cell responsesTh2-polarized immune responseCross-reactive T cellsAlters immune functionHuman autoimmune diseasesAcetate inducesCross-reactive responsesT cell receptorT cell linesImmune deviationMost patientsTh2 typeAutoimmune disordersTh2 cytokinesAutoimmune diseasesDaily injectionsIL-13IL-5Th2 cellsHealthy subjectsImmune response
1999
T cell Autoreactivity to Proinsulin Epitopes in Diabetic Patients and Healthy Subjects
Semana G, Gausling R, Jackson R, Hafler D. T cell Autoreactivity to Proinsulin Epitopes in Diabetic Patients and Healthy Subjects. Journal Of Autoimmunity 1999, 12: 259-267. PMID: 10330297, DOI: 10.1006/jaut.1999.0282.Peer-Reviewed Original ResearchConceptsProinsulin epitopesImmune responseProliferative responseReactive cellsPeptide-specific T cellsShort-term cell linesSpecific T cell clonesHigher 3H-thymidine incorporationPredominant immune responseT cell autoreactivitySpecific T cellsLow proliferative responseTissue-specific autoantigensT cell clonesCD3-CD28IDDM groupIDDM patientsDiabetic patientsControl subjectsDisease onsetPotential autoantigensStrong TCR signalsC-peptideT cellsHealthy subjectsCross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein
Ausubel L, Bieganowska K, Hafler D. Cross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein. Cellular Immunology 1999, 193: 99-107. PMID: 10202117, DOI: 10.1006/cimm.1998.1447.Peer-Reviewed Original ResearchConceptsT cell clonesT cellsSpecific T cell repertoireAutoreactive T cellsTh1-type cytokinesTh2-type cytokinesMultiple sclerosis patientsT cell repertoireAltered peptide ligandT cell receptor alphaPotential beneficial effectsTCR contact residuesMyelin basic proteinDownregulatory cytokinesSclerosis patientsIL-4IL-5Individual patientsReceptor alphaBeneficial effectsClonal expansionCytokinesPeptide ligandsSubstantial proliferationCross reactivityDirect analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy.
Bieganowska K, Höllsberg P, Buckle G, Lim D, Greten T, Schneck J, Altman J, Jacobson S, Ledis S, Hanchard B, Chin J, Morgan O, Roth P, Hafler D. Direct analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy. The Journal Of Immunology 1999, 162: 1765-71. PMID: 9973440, DOI: 10.4049/jimmunol.162.3.1765.Peer-Reviewed Original ResearchMeSH KeywordsAdultB7-1 AntigenCD28 AntigensCD8-Positive T-LymphocytesFemaleGene Products, taxHLA-A2 AntigenHuman T-lymphotropic virus 1HumansLymphocyte ActivationMaleMiddle AgedParaparesis, Tropical SpasticPeptide FragmentsPhenotypeProtein ConformationReceptors, Antigen, T-Cell, alpha-betaReceptors, ChemokineReceptors, Interleukin-2SolubilityConceptsT cellsIL-2RMHC class I tetramersHuman T-cell lymphotropic virusViral-specific CD8Class I tetramersProgressive neurologic diseaseDifferent chemokine receptorsHLA-A2 alleleCentral nervous systemTCR Vbeta chainsReactive CD8TCR usageInflammatory infiltrateVbeta chainsChemokine receptorsNeurologic diseaseImmune responseCD8Lymphotropic virusMyelopathyNervous systemPatientsHTLVClonal expansion
1997
Changes in cytokine secretion induced by altered peptide ligands of myelin basic protein peptide 85-99.
Ausubel LJ, Krieger JI, Hafler DA. Changes in cytokine secretion induced by altered peptide ligands of myelin basic protein peptide 85-99. The Journal Of Immunology 1997, 159: 2502-12. PMID: 9278344, DOI: 10.4049/jimmunol.159.5.2502.Peer-Reviewed Original ResearchAutoimmune DiseasesCell DifferentiationCell LineClone CellsGene Rearrangement, T-LymphocyteHumansImmunodominant EpitopesInterferon-gammaInterleukin-4Interleukin-5Lymphocyte ActivationMultiple SclerosisMyelin Basic ProteinPeptide FragmentsReceptors, Antigen, T-Cell, alpha-betaStructure-Activity RelationshipT-Lymphocyte SubsetsTh1 CellsTh2 CellsWeak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones.
Anderson DE, Ausubel LJ, Krieger J, Höllsberg P, Freeman GJ, Hafler DA. Weak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones. The Journal Of Immunology 1997, 159: 1669-75. PMID: 9257827, DOI: 10.4049/jimmunol.159.4.1669.Peer-Reviewed Original Research
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
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 sequencesStructural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones.
Wucherpfennig KW, Sette A, Southwood S, Oseroff C, Matsui M, Strominger JL, Hafler DA. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. Journal Of Experimental Medicine 1994, 179: 279-290. PMID: 7505801, PMCID: PMC2191316, DOI: 10.1084/jem.179.1.279.Peer-Reviewed Original ResearchConceptsT cell clonesMyelin basic proteinMultiple sclerosisCell clonesT cellsImmunodominant myelin basic protein peptideMBP-reactive T cellsMajor histocompatibility complex class IIDR2 haplotypeHistocompatibility complex class IIImmunodominant T cell epitopesHuman T cell clonesAutoreactive T cellsReactive T cellsT cell epitopesMyelin basic protein peptideT cell stimulationT cell receptorMS patientsDRB1 moleculesDR2 antigenRestriction elementsCell epitopesTarget antigenClass II
1993
T-cell presentation of antigen requires cell-to-cell contact for proliferation and anergy induction. Differential MHC requirements for superantigen and autoantigen.
LaSalle JM, Toneguzzo F, Saadeh M, Golan DE, Taber R, Hafler DA. T-cell presentation of antigen requires cell-to-cell contact for proliferation and anergy induction. Differential MHC requirements for superantigen and autoantigen. The Journal Of Immunology 1993, 151: 649-57. PMID: 7687620, DOI: 10.4049/jimmunol.151.2.649.Peer-Reviewed Original ResearchConceptsStaphylococcal enterotoxin BT cell clonesT cellsT cell presentationAnergy inductionCalcium fluxMHC classCell contactHuman T cell clonesCell interactionsT cell coculturesT cell responsesMHC class IIT cell interactionsT cell migrationIndividual T cellsSingle T cellsSubsequent anergyHLA-DRIndividual CD4Class IIAnergyEnterotoxin BSuperantigensSelf-Stimulation
1990
T-cell recognition of an immuno-dominant myelin basic protein epitope in multiple sclerosis
Ota K, Matsui M, Milford E, Mackin G, Weiner H, Hafler D. T-cell recognition of an immuno-dominant myelin basic protein epitope in multiple sclerosis. Nature 1990, 346: 183-187. PMID: 1694970, DOI: 10.1038/346183a0.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAntigen-Presenting CellsApoproteinsAutoantigensCells, CulturedEpitopesHLA-DR AntigensHumansIn Vitro TechniquesMajor Histocompatibility ComplexMolecular Sequence DataMultiple SclerosisMyelin Basic ProteinMyelin ProteinsMyelin Proteolipid ProteinPeptide FragmentsT-LymphocytesConceptsMultiple sclerosis patientsT cell linesMyelin basic proteinMultiple sclerosisSclerosis patientsT cellsVivo-activated T cellsShort-term T cell linesMyelin basic protein epitopeBasic proteinExperimental autoimmune encephalomyelitisDifferent T-cell linesCentral nervous systemMultiple sclerosis subjectsT cell recognitionT cell specificityAutoimmune encephalomyelitisImmune involvementAutoimmune diseasesPotential autoantigensNormal controlsNervous systemNeurological diseasesSclerosisPatients