2022
Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Unterman A, Sumida TS, Nouri N, Yan X, Zhao AY, Gasque V, Schupp JC, Asashima H, Liu Y, Cosme C, Deng W, Chen M, Raredon MSB, Hoehn KB, Wang G, Wang Z, DeIuliis G, Ravindra NG, Li N, Castaldi C, Wong P, Fournier J, Bermejo S, Sharma L, Casanovas-Massana A, Vogels CBF, Wyllie AL, Grubaugh ND, Melillo A, Meng H, Stein Y, Minasyan M, Mohanty S, Ruff WE, Cohen I, Raddassi K, Niklason L, Ko A, Montgomery R, Farhadian S, Iwasaki A, Shaw A, van Dijk D, Zhao H, Kleinstein S, Hafler D, Kaminski N, Dela Cruz C. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nature Communications 2022, 13: 440. PMID: 35064122, PMCID: PMC8782894, DOI: 10.1038/s41467-021-27716-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAgedAntibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCells, CulturedCOVID-19COVID-19 Drug TreatmentFemaleGene Expression ProfilingGene Expression RegulationHumansImmunity, InnateMaleReceptors, Antigen, B-CellReceptors, Antigen, T-CellRNA-SeqSARS-CoV-2Single-Cell AnalysisConceptsProgressive COVID-19B cell clonesSingle-cell analysisT cellsImmune responseMulti-omics single-cell analysisCOVID-19Cell clonesAdaptive immune interactionsSevere COVID-19Dynamic immune responsesGene expressionSARS-CoV-2 virusAdaptive immune systemSomatic hypermutation frequenciesCellular effectsProtein markersEffector CD8Immune signaturesProgressive diseaseHypermutation frequencyProgressive courseClassical monocytesClonesImmune interactions
2018
Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity
Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DA. Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nature Immunology 2018, 19: 1391-1402. PMID: 30374130, PMCID: PMC6240373, DOI: 10.1038/s41590-018-0236-6.Peer-Reviewed Original ResearchConceptsProstaglandin E receptor 2Regulatory T cellsTreg cellsT cellsAnti-inflammatory cytokine productionIL-10 productionPeripheral immune toleranceIL-10 expressionΒ-cateninE receptor 2Treg subpopulationsTreg phenotypeIL-10Cytokines IFNImmune toleranceTreg signatureCytokine signatureMultiple sclerosisAutoimmune diseasesCytokine productionInflammatory environmentLethal autoimmunityReceptor 2Activated β-cateninIFN
2016
TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage
Taylor RA, Chang CF, Goods BA, Hammond MD, Grory B, Ai Y, Steinschneider AF, Renfroe SC, Askenase MH, McCullough LD, Kasner SE, Mullen MT, Hafler DA, Love JC, Sansing LH. TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. Journal Of Clinical Investigation 2016, 127: 280-292. PMID: 27893460, PMCID: PMC5199690, DOI: 10.1172/jci88647.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain InjuriesCerebral HemorrhageGene Expression RegulationInterleukin-6MiceMice, TransgenicMicrogliaRecovery of FunctionSignal TransductionTransforming Growth Factor beta1ConceptsIntracerebral hemorrhageTGF-β1 treatmentTGF-β1Functional recoveryBrain injuryMurine modelPlasma TGF-β1 concentrationResolution phasePhenotype of microgliaTissue-resident microgliaAcute brain injuryBlood-derived macrophagesTGF-β1 concentrationsRapid inflammatory reactionIL6 gene expressionLongitudinal transcriptional profilingInflammatory profileMicroglial phenotypeFunctional outcomeBrain parenchymaInflammatory reactionPromotes recoveryMicrogliaTherapeutic targetDevastating form
2015
Genetic basis of autoimmunity
Marson A, Housley WJ, Hafler DA. Genetic basis of autoimmunity. Journal Of Clinical Investigation 2015, 125: 2234-2241. PMID: 26030227, PMCID: PMC4497748, DOI: 10.1172/jci78086.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmune DiseasesAutoimmunityDatabases, GeneticGene Expression RegulationGene-Environment InteractionGenome-Wide Association StudyHumansConceptsGenetic basisInterpretation of GWASMultiple genomic datasetsWide association studyCommon human autoimmune diseasesRelevant cell typesCellular conditionsCellular phenotypesGenomic datasetsGene expressionDense genotypingBiological pathwaysAssociation studiesHuman autoimmune diseasesNucleotide variantsCell typesAutoimmune diseasesPrimary immune cellsUnbiased viewMonogenic mutationsPolygenic risk factorsEssential mechanismComplex disorderEnvironmental factorsNovel diagnostics
2014
Prolonged Proinflammatory Cytokine Production in Monocytes Modulated by Interleukin 10 After Influenza Vaccination in Older Adults
Mohanty S, Joshi SR, Ueda I, Wilson J, Blevins TP, Siconolfi B, Meng H, Devine L, Raddassi K, Tsang S, Belshe RB, Hafler DA, Kaech SM, Kleinstein SH, Trentalange M, Allore HG, Shaw AC. Prolonged Proinflammatory Cytokine Production in Monocytes Modulated by Interleukin 10 After Influenza Vaccination in Older Adults. The Journal Of Infectious Diseases 2014, 211: 1174-1184. PMID: 25367297, PMCID: PMC4366602, DOI: 10.1093/infdis/jiu573.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedCytokinesDual Specificity Phosphatase 1FemaleGene Expression RegulationGPI-Linked ProteinsHumansImmunity, InnateInfluenza VaccinesInfluenza, HumanInterleukin-10Interleukin-6Lipopolysaccharide ReceptorsMaleMonocytesPhosphorylationReceptors, IgGSignal TransductionSTAT3 Transcription FactorTumor Necrosis Factor-alphaVaccinationYoung AdultConceptsOlder adultsInfluenza vaccinationInflammatory monocytesInterleukin-10Cytokine productionOlder subjectsAnti-inflammatory cytokine interleukin-10Influenza vaccine antibody responseTumor necrosis factor αImpaired vaccine responsesVaccine antibody responseIL-10 productionCytokine interleukin-10Proinflammatory cytokine productionNecrosis factor αAge-associated elevationPhosphorylated signal transducerVaccine responsesAntibody responseInterleukin-6Immune responseMonocyte populationsDay 28Intracellular stainingVaccinationEnhanced 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 functionTreg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses
Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, Sharpe AH, Quintana FJ, Mathis D, Benoist C, Hafler DA, Kuchroo VK. Treg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses. Immunity 2014, 40: 569-581. PMID: 24745333, PMCID: PMC4070748, DOI: 10.1016/j.immuni.2014.02.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationCells, CulturedCytokinesEosinophilsFibrinogenForkhead Transcription FactorsGene Expression ProfilingGene Expression RegulationImmunosuppression TherapyLymphocyte ActivationMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicReceptors, ImmunologicRespiratory HypersensitivityTh1-Th2 BalanceT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryConceptsTreg cell subsetsTh2 cell responsesTreg cellsCell subsetsCell responsesProinflammatory T helper 1T effector cell proliferationTreg cell-mediated suppressionFibrinogen-like protein 2Allergic airway inflammationT regulatory (Treg) cellsTh2 cytokine productionSuppression of Th1T helper 1Effector cell proliferationTreg signature genesProinflammatory Th1TIGIT expressionAirway inflammationTh17 cellsRegulatory cellsHelper 1Cytokine productionT cellsImmune response
2013
Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus
Ottoboni L, Frohlich IY, Lee M, Healy BC, Keenan BT, Xia Z, Chitnis T, Guttmann CR, Khoury SJ, Weiner HL, Hafler DA, De Jager PL. Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. Neurology 2013, 81: 1891-1899. PMID: 24174586, PMCID: PMC3843384, DOI: 10.1212/01.wnl.0000436612.66328.8a.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArginineChemokine CXCL10FemaleGene Expression RegulationGenetic Predisposition to DiseaseGenotypeGlutamineHEK293 CellsHumansImmunologic FactorsLongitudinal StudiesMaleMonocytesMultiple SclerosisMutationPhorbol EstersReceptors, Tumor Necrosis Factor, Type IRNA IsoformsSignal TransductionTumor Necrosis Factor-alphaConceptsTNFRSF1A locusSusceptibility allelesFunctional consequencesRobust transcriptional responseTranscriptional responseCytoplasmic domainRNA isoformsTNF-α stimulationRho GTPaseMS susceptibility genesMS geneG proteinsSusceptibility genesMolecular levelTNF pathwayGenesAltered expressionLociTNF-α pathwayAllelesRisk allelesPathwayGTPaseImmune functionTransmembraneThe 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
2012
Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression
Kickler K, Maltby K, Choileain S, Stephen J, Wright S, Hafler DA, Jabbour HN, Astier AL. Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression. The Journal Of Immunology 2012, 188: 5303-5310. PMID: 22544928, PMCID: PMC3758685, DOI: 10.4049/jimmunol.1103090.Peer-Reviewed Original ResearchConceptsG protein-coupled receptor kinasesCell functionProtein-coupled receptor kinasesT cell functionT cell activationG protein-coupled receptorsProtein-coupled receptorsCD46 expressionPrimary T cellsReceptor kinaseT cellsCD46 functionsCell activationRegulatory mechanismsDiverse rolesDifferentiation pathwayNovel roleCytokine productionProstanoid familyActivation signalsActivated T cellsT cell responsesChronic inflammatory diseaseSubtypes of receptorsCD46 activationThe TIGIT/CD226 Axis Regulates Human T Cell Function
Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 Axis Regulates Human T Cell Function. The Journal Of Immunology 2012, 188: 3869-3875. PMID: 22427644, PMCID: PMC3324669, DOI: 10.4049/jimmunol.1103627.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, Differentiation, T-LymphocyteCD4-Positive T-LymphocytesCell CommunicationCell ProliferationCells, CulturedCytokinesDendritic CellsGATA3 Transcription FactorGene Expression RegulationHumansImmune ToleranceReceptors, ImmunologicReceptors, VirusRNA, Small InterferingSignal TransductionT-Box Domain ProteinsConceptsT cell functionT cellsAutoimmune diseasesT-betTIGIT/CD226 axisHuman T cell responsesT cell-intrinsic mannerHuman T cell functionAlternative costimulatory pathwaysT cell responsesCell functionDendritic cell surfaceHuman autoimmune diseasesIL-10 expressionT cell IgIFN regulatory factor 4T cell proliferationOrphan receptor CDirect inhibitory effectIFN-γ mRNACell-intrinsic mannerRegulatory factor 4TIGIT expressionTIGIT knockdownTolerogenic phenotype
2010
TGF-β Induces IL-9 Production from Human Th17 Cells
Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T, Elyaman W, Khoury SJ, Kuchroo VK, Baecher-Allan C, Hafler DA. TGF-β Induces IL-9 Production from Human Th17 Cells. The Journal Of Immunology 2010, 185: 46-54. PMID: 20498357, PMCID: PMC2936106, DOI: 10.4049/jimmunol.1000356.Peer-Reviewed Original ResearchMeSH KeywordsAdultCell PolarityCells, CulturedCoculture TechniquesDiabetes Mellitus, Type 1Gene Expression RegulationHumansImmunohistochemistryInflammation MediatorsInterleukin-17Interleukin-9Middle AgedResting Phase, Cell CycleT-Lymphocytes, Helper-InducerTransforming Growth Factor beta1Young AdultConceptsCD4 T cellsIL-9 productionIL-17IL-9IL-1betaCD4 cellsProinflammatory cytokinesT cellsNaive cellsIL-9/ILCD4 T cell subsetsMemory CD4 T cellsNaive CD4 T cellsHuman naive CD4 T cellsTh17-inducing cytokinesT cell subsetsHuman autoimmune diseasesAutoimmune diabetesMemory CD4Th17 cellsTh2 cytokinesAutoimmune diseasesCell subsetsIL-4Inflammatory conditions
2009
RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels
Astier AL, Beriou G, Eisenhaure TM, Anderton SM, Hafler DA, Hacohen N. RNA Interference Screen in Primary Human T Cells Reveals FLT3 as a Modulator of IL-10 Levels. The Journal Of Immunology 2009, 184: 685-693. PMID: 20018615, PMCID: PMC3746748, DOI: 10.4049/jimmunol.0902443.Peer-Reviewed Original ResearchConceptsIL-10 levelsRegulatory type 1 (Tr1) cellsIL-10 secretionIL-10 productionT cellsType 1 cellsHuman T cellsIL-10Primary human T cellsPotent anti-inflammatory cytokineHematopoeitic growth factorsAnti-inflammatory cytokinesHuman primary immune cellsT cell functionActivated T cellsAddition of FLPrimary immune cellsT cell activationRegulatory cellsNovel regulatory feedback loopImmune cellsSuppressive activityCell activationFLT3Growth factorDe novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot
Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, Ergul E, Conta JH, Korn JM, McCarroll SA, Gorham JM, Gabriel S, Altshuler DM, de Lourdes Quintanilla-Dieck M, Artunduaga MA, Eavey RD, Plenge RM, Shadick NA, Weinblatt ME, De Jager PL, Hafler DA, Breitbart RE, Seidman JG, Seidman CE. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nature Genetics 2009, 41: 931-935. PMID: 19597493, PMCID: PMC2747103, DOI: 10.1038/ng.415.Peer-Reviewed Original Research
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 ResearchLack of TIM-3 Immunoregulation in Multiple Sclerosis
Yang L, Anderson DE, Kuchroo J, Hafler DA. Lack of TIM-3 Immunoregulation in Multiple Sclerosis. The Journal Of Immunology 2008, 180: 4409-4414. PMID: 18354161, DOI: 10.4049/jimmunol.180.7.4409.Peer-Reviewed Original ResearchMeSH KeywordsAdultApoptosisCD4-Positive T-LymphocytesCells, CulturedGene Expression RegulationHepatitis A Virus Cellular Receptor 2HumansInterferon-gammaMembrane ProteinsMultiple SclerosisConceptsMultiple sclerosisT cell functionTim-3Untreated patientsTreatment of MSType 1 Th cellsBlocking Tim-3Tim-3 functionTim-3 regulationT-cell infiltratesTim-3 expressionPeripheral immune systemCell functionHuman autoimmune diseasesIFN-gamma secretionCNS white matterT cell stimulationHuman Tim-3Cell infiltrateGlatiramer acetateImmune toleranceAutoimmune diseasesControl subjectsTh cellsInflammatory diseases
2006
Dysregulated T cell expression of TIM3 in multiple sclerosis
Koguchi K, Anderson DE, Yang L, O'Connor KC, Kuchroo VK, Hafler DA. Dysregulated T cell expression of TIM3 in multiple sclerosis. Journal Of Experimental Medicine 2006, 203: 1413-1418. PMID: 16754722, PMCID: PMC2118310, DOI: 10.1084/jem.20060210.Peer-Reviewed Original ResearchMeSH KeywordsClone CellsGene Expression RegulationHepatitis A Virus Cellular Receptor 2HumansLymphocyte ActivationMembrane ProteinsMultiple SclerosisReceptors, VirusT-LymphocytesConceptsIFN-gamma secretionCSF clonesT cell expressionMultiple sclerosisT cellsHuman T cellsTIM3 expressionControl subjectsCerebrospinal fluidCell expressionMucin-domain-containing moleculesPathogenesis of MSEx vivo CD4Human autoimmune diseasesT helper cellsT-cell immunoglobulinT cell clonesVivo CD4Costimulatory blockadeTh1 responseCytokine profileCell surface moleculesAutoimmune diseasesHelper cellsInterleukin-12
2004
T Cell Ig- and Mucin-Domain-Containing Molecule-3 (TIM-3) and TIM-1 Molecules Are Differentially Expressed on Human Th1 and Th2 Cells and in Cerebrospinal Fluid-Derived Mononuclear Cells in Multiple Sclerosis
Khademi M, Illés Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, Hafler DA, Kuchroo VK, Olsson T, Piehl F, Wallström E. T Cell Ig- and Mucin-Domain-Containing Molecule-3 (TIM-3) and TIM-1 Molecules Are Differentially Expressed on Human Th1 and Th2 Cells and in Cerebrospinal Fluid-Derived Mononuclear Cells in Multiple Sclerosis. The Journal Of Immunology 2004, 172: 7169-7176. PMID: 15153541, DOI: 10.4049/jimmunol.172.11.7169.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedCell LineCell PolarityCerebrospinal FluidCytokinesFemaleGene Expression RegulationHepatitis A Virus Cellular Receptor 1Hepatitis A Virus Cellular Receptor 2HumansMaleMembrane GlycoproteinsMembrane ProteinsMiddle AgedMultiple SclerosisReceptors, VirusRNA, MessengerTh1 CellsTh2 CellsConceptsCerebrospinal fluid mononuclear cellsFluid mononuclear cellsT cell IgMononuclear cellsTim-3Multiple sclerosisTh2 cellsTIM-1Human Th1TIM moleculesMucin-domain-containing moleculesTim-3 mRNA levelsTh2-mediated diseasesHigh expressionExperimental autoimmune encephalomyelitisHuman autoimmune diseasesTIM-1 expressionIFN-gamma mRNAReal-time RT-PCRTim-1 polymorphismsTh1 cell clonesHigher mRNA expressionAirway hyperreactivityClinical remissionAutoimmune encephalomyelitis
2000
Multiple differences in gene expression in regulatory Vα24JαQ T cells from identical twins discordant for type I diabetes
Wilson S, Kent S, Horton H, Hill A, Bollyky P, Hafler D, Strominger J, Byrne M. Multiple differences in gene expression in regulatory Vα24JαQ T cells from identical twins discordant for type I diabetes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 7411-7416. PMID: 10840051, PMCID: PMC16559, DOI: 10.1073/pnas.120161297.Peer-Reviewed Original ResearchMeSH KeywordsDiabetes Mellitus, Type 1Gene Expression RegulationHumansImmunoglobulin Variable RegionReceptors, Antigen, T-Cell, alpha-betaT-LymphocytesTwinsConceptsT cell receptor activationCell receptor activationT cellsTranscriptional consequencesDNA microarraysGene expressionActivation of cellsMyeloid lineageClonesMurine autoimmune diseaseInvariant T (MAIT) cellsIL-4 secretionType 1 diabetesAnti-CD3 stimulationT cell clonesIdentical twinsMRNA levelsReceptor activationCellsCell clonesAutoimmune diseasesActivationSecreting clonesQualitative defectsMultiple differences