2023
PD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection
Asashima H, Mohanty S, Comi M, Ruff W, Hoehn K, Wong P, Klein J, Lucas C, Cohen I, Coffey S, Lele N, Greta L, Raddassi K, Chaudhary O, Unterman A, Emu B, Kleinstein S, Montgomery R, Iwasaki A, Dela Cruz C, Kaminski N, Shaw A, Hafler D, Sumida T. PD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection. Cell Reports 2023, 42: 111895. PMID: 36596303, PMCID: PMC9806868, DOI: 10.1016/j.celrep.2022.111895.Peer-Reviewed Original ResearchConceptsAcute viral infectionTph cellsViral infectionCXCR3 expressionClinical outcomesHelper TSevere viral infectionsB cell helpBetter clinical outcomesProtective humoral immunityT cell-B cell interactionsKey immune responsesPlasmablast expansionB cell differentiationCell subsetsHumoral immunityCell helpImmune responseInterferon γPlasmablast differentiationB cellsPlasmablastsCell responsesInfectionCD4
2018
Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization
Fuchs A, Gliwiński M, Grageda N, Spiering R, Abbas AK, Appel S, Bacchetta R, Battaglia M, Berglund D, Blazar B, Bluestone JA, Bornhäuser M, Brinke A, Brusko TM, Cools N, Cuturi MC, Geissler E, Giannoukakis N, Gołab K, Hafler DA, van Ham SM, Hester J, Hippen K, Di Ianni M, Ilic N, Isaacs J, Issa F, Iwaszkiewicz-Grześ D, Jaeckel E, Joosten I, Klatzmann D, Koenen H, van Kooten C, Korsgren O, Kretschmer K, Levings M, Marek-Trzonkowska NM, Martinez-Llordella M, Miljkovic D, Mills KHG, Miranda JP, Piccirillo CA, Putnam AL, Ritter T, Roncarolo MG, Sakaguchi S, Sánchez-Ramón S, Sawitzki B, Sofronic-Milosavljevic L, Sykes M, Tang Q, Vives-Pi M, Waldmann H, Witkowski P, Wood KJ, Gregori S, Hilkens CMU, Lombardi G, Lord P, Martinez-Caceres EM, Trzonkowski P. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization. Frontiers In Immunology 2018, 8: 1844. PMID: 29379498, PMCID: PMC5775516, DOI: 10.3389/fimmu.2017.01844.Peer-Reviewed Original ResearchAntigen-presenting cellsRegulatory cellsTolerogenic antigen-presenting cellsT regulatory (Treg) cellsClinical applicationPosttransplant complicationsTreg preparationsAllergic diseasesClinical trialsTregsEfficacious treatmentTreg productsCellular therapyStandardized reportingMedicinal productsDifferent preparationsCellsInvestigatorsCD4ComplicationsTherapyDiseaseTrials
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
TLR7 induces anergy in human CD4+ T cells
Dominguez-Villar M, Gautron AS, de Marcken M, Keller MJ, Hafler DA. TLR7 induces anergy in human CD4+ T cells. Nature Immunology 2014, 16: 118-128. PMID: 25401424, PMCID: PMC4413902, DOI: 10.1038/ni.3036.Peer-Reviewed Original ResearchDecreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells
Kofler DM, Marson A, Dominguez-Villar M, Xiao S, Kuchroo VK, Hafler DA. Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. Journal Of Clinical Investigation 2014, 124: 2513-2522. PMID: 24812667, PMCID: PMC4089462, DOI: 10.1172/jci72973.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAutoimmunityCase-Control StudiesDinoprostoneDown-RegulationFemaleGene Knockdown TechniquesGene SilencingHumansMaleMiceMice, Inbred C57BLMice, KnockoutMiddle AgedModels, ImmunologicalMultiple SclerosisNuclear Receptor Subfamily 1, Group F, Member 3PhenotypePromoter Regions, GeneticReceptors, Prostaglandin E, EP2 SubtypeSignal TransductionTh17 CellsConceptsTh17 cell phenotypeProstaglandin receptor EP2Receptor EP2Healthy individualsOverexpression of EP2Transcription factor RORCT cell subsetsEffects of PGE2Cell phenotypeExpression of IFNInflammatory gene transcriptionPGE2-dependent pathwayTh17 cellsWT miceAutoimmune diseasesCell subsetsHealthy subjectsEP2 expressionGM-CSFEP2RORCCD4Cell typesCellsGene transcription
2013
Increased Frequencies of Myelin Reactive CCR6+ Pathogenic IL-17/GM-CSF/IFNγ Secreting CD4+ T Cells in Patients with Multiple Sclerosis (P03.225)
Cao Y, Raddassi K, Hafler D. Increased Frequencies of Myelin Reactive CCR6+ Pathogenic IL-17/GM-CSF/IFNγ Secreting CD4+ T Cells in Patients with Multiple Sclerosis (P03.225). Neurology 2013, 80 DOI: 10.1212/wnl.80.7_supplement.p03.225.Peer-Reviewed Original Research
2009
On-Chip Activation and Subsequent Detection of Individual Antigen-Specific T Cells
Song Q, Han Q, Bradshaw EM, Kent SC, Raddassi K, Nilsson B, Nepom GT, Hafler DA, Love JC. On-Chip Activation and Subsequent Detection of Individual Antigen-Specific T Cells. Analytical Chemistry 2009, 82: 473-477. PMID: 20000848, PMCID: PMC2828941, DOI: 10.1021/ac9024363.Peer-Reviewed Original ResearchConceptsAntigen-specific T cellsAntigen-specific CD4T cellsAntigen-specific mannerType 1 diabetesMajor histocompatibility complex receptorIndividual CD4Multiple sclerosisAutoimmune diseasesPrimary T cellsCD4Subnanoliter wellsClinical samplesNumber of cellsComplex receptorSubsequent assessmentHuman tissuesCellsChip activationVivoActivationSclerosisDiabetesCytokinesDisease
2008
IL-21 and TGF-β are required for differentiation of human TH17 cells
Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 2008, 454: 350-352. PMID: 18469800, PMCID: PMC2760130, DOI: 10.1038/nature07021.Peer-Reviewed Original Research
2007
Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells
Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA. Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells. Science 2007, 318: 1141-1143. PMID: 18006747, DOI: 10.1126/science.1148536.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesCD11b AntigenCentral Nervous System NeoplasmsDendritic CellsEncephalomyelitis, Autoimmune, ExperimentalGalectinsGlioblastomaHepatitis A Virus Cellular Receptor 2HumansImmunity, InnateInflammation MediatorsLipopolysaccharidesMacrophagesMembrane ProteinsMiceMicrogliaMultiple SclerosisRatsReceptors, ImmunologicReceptors, VirusSignal TransductionTh1 CellsT-LymphocytesToll-Like ReceptorsConceptsImmune receptor Tim-3Tim-3Immune cellsT helper 1 cellsAdaptive immune cellsInnate immune cellsToll-like receptorsInduced Immune ResponsesInnate immune systemTh1 immunityDendritic cellsTissue inflammationInflammatory conditionsT cellsImmune responseImmune systemImportant mediatorAntibody agonistsInflammationCell typesLatter findingNumerous pathwaysCellsDifferential expressionCD4Multispecific 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
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 protein
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 signal
1999
Noncanonical Vα24JαQ T cells with conservative α chain CDR3 region amino acid substitutions are restricted by CD1d
Kent S, Hafler D, Strominger J, Wilson S. Noncanonical Vα24JαQ T cells with conservative α chain CDR3 region amino acid substitutions are restricted by CD1d. Human Immunology 1999, 60: 1080-1089. PMID: 10600006, DOI: 10.1016/s0198-8859(99)00109-3.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAntigens, CD1Antigens, CD1dBase SequenceClone CellsComplementarity Determining RegionsConserved SequenceDNAGene Rearrangement, alpha-Chain T-Cell Antigen ReceptorHumansImmunoglobulin Variable RegionImmunophenotypingKiller Cells, NaturalReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsConceptsT cell receptorT cellsCD1d restrictionPeripheral blood mononuclear cellsBlood mononuclear cellsAmino acid substitutionsAlpha chainSingle amino acid substitutionHuman CD161Total CD4Mononuclear cellsInterleukin-4Surface phenotypeRestriction elementsCD4Acid substitutionsCD1dCDR3 residuesJ rearrangementsJ junctionsVariant clonesChain transcriptsCellsJalpha18Valpha24Differential 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
1996
Increased IL-12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand
Weiner H, Balashov K, Smith D, Khoury S, Hafler D. Increased IL-12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand. Multiple Sclerosis Journal 1996, 2: 253-253. DOI: 10.1177/135245859600200519.Peer-Reviewed Original Research
1988
Loss of functional suppression is linked to decreases in circulating suppressor inducer (CD4 + 2H4 +) T Cells in multiple sclerosis
Chofflon M, Weiner H, Morimoto C, Hafler D. Loss of functional suppression is linked to decreases in circulating suppressor inducer (CD4 + 2H4 +) T Cells in multiple sclerosis. Annals Of Neurology 1988, 24: 185-191. PMID: 2972249, DOI: 10.1002/ana.410240203.Peer-Reviewed Original ResearchConceptsSuppressor-inducer T cellsProgressive multiple sclerosisInducer T cellsSuppressor T cellsMultiple sclerosisT cellsFunctional suppressionTwo-color immunofluorescenceImmunoregulatory abnormalitiesImmunological findingsIgG synthesisMononuclear cellsPokeweed mitogenImmunoglobulin synthesisNormal subjectsSclerosisCD4Neurological diseasesAMLRPatientsTwo-stage assaySuppressor functionSignificant correlationPresent studyCellsThe 2H4 (CD45R) antigen is selectively decreased in multiple sclerosis lesions.
Sobel RA, Hafler DA, Castro EE, Morimoto C, Weiner HL. The 2H4 (CD45R) antigen is selectively decreased in multiple sclerosis lesions. The Journal Of Immunology 1988, 140: 2210-4. PMID: 2965183, DOI: 10.4049/jimmunol.140.7.2210.Peer-Reviewed Original ResearchConceptsMultiple sclerosisViral encephalitisImmune responseCentral nervous system immune responseSuppressor-inducer functionCentral nervous system tissuePlaque edgeAdjacent white matterIL-2R mAbNervous system tissueMultiple sclerosis lesionsAnti-2H4Anti-CD4Inflammatory cellsMS plaquesImmunohistochemical stainingWhite matterSclerosis lesionsEncephalitisPatientsCellsRare cellsCD8CD4SclerosisRegulation of T cell clone function via CD4 and CD8 molecules. Anti-CD4 can mediate two distinct inhibitory activities.
Blue ML, Hafler DA, Daley JF, Levine H, Craig KA, Breitmeyer JB, Schlossman SF. Regulation of T cell clone function via CD4 and CD8 molecules. Anti-CD4 can mediate two distinct inhibitory activities. The Journal Of Immunology 1988, 140: 376-83. PMID: 2891768, DOI: 10.4049/jimmunol.140.2.376.Peer-Reviewed Original ResearchConceptsReceptor functionAnti-CD4Anti-CD8 monoclonal antibodiesCD3-TiCell receptor functionMajor histocompatibility complex moleculesIntracellular free Ca2CD3 T-cell receptorT cell activationHistocompatibility complex moleculesCytotoxic functionT cell receptor functionCD8 moleculesCD4CD8Distinct inhibitory activityCD4 moleculeCell activationAntigen receptor functionCell receptorMonoclonal antibodiesFree Ca2Dependent proliferationFunctional effectsSoluble antibodies
1987
Phosphorylation of CD4 and CD8 molecules following T cell triggering.
Blue ML, Hafler DA, Craig KA, Levine H, Schlossman SF. Phosphorylation of CD4 and CD8 molecules following T cell triggering. The Journal Of Immunology 1987, 139: 3949-54. PMID: 2961801, DOI: 10.4049/jimmunol.139.12.3949.Peer-Reviewed Original ResearchConceptsCell receptor complexCD3-T cell receptor complexT cell triggeringReceptor complexPhorbol myristate acetate (PMA) treatmentMolecular signaling mechanismsDifferent receptor pathwaysErythrocyte binding proteinCD8 moleculesSignaling mechanismBinding proteinPhosphorylationCell triggeringT cell activationCD2 pathwayT cellsReceptor pathwayMolecular modificationsT cell clonesCell activationCell clonesPathwayActivationCD4Cells