2024
An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction
Sumida T, Lincoln M, He L, Park Y, Ota M, Oguchi A, Son R, Yi A, Stillwell H, Leissa G, Fujio K, Murakawa Y, Kulminski A, Epstein C, Bernstein B, Kellis M, Hafler D. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction. Science Translational Medicine 2024, 16: eadp1720. PMID: 39196959, DOI: 10.1126/scitranslmed.adp1720.Peer-Reviewed Original ResearchConceptsForkhead box P3Autoimmune diseasesCD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cellsMultiple sclerosisFoxp3<sup>+</sup> regulatory T cellsRegulatory T cell dysfunctionPR domain zinc finger protein 1Zinc finger protein 1Glucocorticoid-regulated kinase 1Regulatory T cellsT cell dysfunctionDisorder of young adultsAutoimmune disease multiple sclerosisDisease multiple sclerosisExpression of serumTranscriptional circuitsEpigenomic profilingShort isoformPrevent autoimmunityUpstream regulatorT cellsHuman autoimmunityEvolutionary emergenceKinase 1Molecular mechanisms
2023
Regulatory T cells in peripheral tissue tolerance and diseases
Cheru N, Hafler D, Sumida T. Regulatory T cells in peripheral tissue tolerance and diseases. Frontiers In Immunology 2023, 14: 1154575. PMID: 37197653, PMCID: PMC10183596, DOI: 10.3389/fimmu.2023.1154575.Peer-Reviewed Original ResearchConceptsTissue-resident TregsRegulatory T cellsT cellsResident TregsTissue TregsAutoimmune diseasesCommon human autoimmune diseasesAutoreactive T cellsHuman autoimmune diseasesNon-immune cellsNon-lymphoid tissuesTissue-resident cellsTreg poolTreg studiesEffector cytokinesPeripheral toleranceTreg functionIPEX syndromeImmune homeostasisSpecific tissue environmentsTregsSuppressive functionLoss of functionResident cellsGene signature
2022
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Axisa P, Yoshida T, Lucca L, Kasler H, Lincoln M, Pham G, Del Priore D, Carpier J, Lucas C, Verdin E, Sumida T, Hafler D. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells. Science Translational Medicine 2022, 14: eabl3651. PMID: 36516268, DOI: 10.1126/scitranslmed.abl3651.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalitisRegulatory T cellsHistone deacetylase 7Multiple sclerosisT cellsMouse modelFunction of Foxp3CD4 T cellsHigher suppressive capacityVivo modelingAutoimmune encephalitisEAE severityImmunosuppressive subsetAutoimmune diseasesImmunomodulatory roleSuppressive capacityImmune cellsDisease onsetDistinct molecular classesSusceptibility lociGenetic susceptibility lociSingle-cell RNA sequencingDisease riskPatient samplesProtective variants
2019
Aedes aegypti AgBR1 antibodies modulate early Zika virus infection of mice
Uraki R, Hastings AK, Marin-Lopez A, Sumida T, Takahashi T, Grover JR, Iwasaki A, Hafler DA, Montgomery RR, Fikrig E. Aedes aegypti AgBR1 antibodies modulate early Zika virus infection of mice. Nature Microbiology 2019, 4: 948-955. PMID: 30858571, PMCID: PMC6533137, DOI: 10.1038/s41564-019-0385-x.Peer-Reviewed Original ResearchConceptsZika virus infectionVirus infectionZika virusAegypti salivary proteinsGuillain-Barre syndromeEarly inflammatory responseSkin of micePrevention of mosquitoInflammatory responseAedes aegypti mosquitoesTherapeutic measuresSalivary factorsSalivary proteinsMosquito-borneInfectionMiceSubstantial mortalityRecent epidemicProtein 1Aegypti mosquitoesAntigenic proteinsVirusAntibodiesMosquitoesAntiserum
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-cateninIFNRegulatory T cells in autoimmune disease
Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nature Immunology 2018, 19: 665-673. PMID: 29925983, PMCID: PMC7882196, DOI: 10.1038/s41590-018-0120-4.Peer-Reviewed Original ResearchConceptsAutoimmune diseasesTreg cellsRegulatory T cell biologyRegulatory T cellsNon-immune cellsTreg cell plasticityTreg cell biologyNew therapeutic strategiesT cell biologyTreg cell instabilityDisease outcomeT cellsTherapeutic strategiesDiseaseCell plasticityCell biologyCellsAutoimmunityPathogenesisSpecific tissuesRegulatory T Cells: From Discovery to Autoimmunity
Kitz A, Singer E, Hafler D. Regulatory T Cells: From Discovery to Autoimmunity. Cold Spring Harbor Perspectives In Medicine 2018, 8: a029041. PMID: 29311129, PMCID: PMC6280708, DOI: 10.1101/cshperspect.a029041.Peer-Reviewed Original ResearchConceptsAutoreactive T cellsT cellsMultiple sclerosisEffector-like T cellsInterferon γ secretionEffector T cellsRegulatory T cellsTreg cell functionT-bet expressionCentral nervous systemT cell activationFunctional TregsΓ secretionProinflammatory cytokinesVitamin DAutoimmune diseasesGenetic predispositionNervous systemLoss of functionReduced suppressionConsistent findingCell functionDisease developmentActivationCells
2017
Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment
Lucca LE, Hafler DA. Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment. Journal Of Clinical Investigation 2017, 127: 1218-1220. PMID: 28319049, PMCID: PMC5373854, DOI: 10.1172/jci93565.Peer-Reviewed Original ResearchConceptsT cellsRecruitment of CD8Antitumor immune responseT cell recruitmentMigration of CD8Cell lung tumorsSyngeneic gliomaChemokines CXCL9Tumor escapeTumor controlImmune infiltrationMetastatic melanomaClinical trialsMalignant gliomasExpression of STAT1Immune surveillanceLung tumorsImmune responseAggressive cancerCell recruitmentCD8Tumor destructionTumorsGliomasCommon mutationsCo‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma
Lucca LE, Hafler DA. Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma. Immunological Reviews 2017, 276: 9-25. PMID: 28258696, PMCID: PMC5338636, DOI: 10.1111/imr.12529.Peer-Reviewed Original ResearchConceptsCheckpoint immunotherapyTumor rejectionCommon adult brain tumorsImmune-related side effectsCheckpoint receptor blockadeCo-inhibitory receptorsIntroduction of immunotherapyT cell exhaustionImmune regulatory pathwaysCo-inhibitory pathwaysAdult brain tumorsPrevention of autoimmunityCentral nervous systemAnti-tumor activityDifferent tumor typesCheckpoint inhibitorsReceptor blockadeAdvanced cancerTherapeutic successBrain tumorsSide effectsImmunotherapyNervous systemTherapeutic efficacyTumor types
2016
Solving Immunology?
Vodovotz Y, Xia A, Read EL, Bassaganya-Riera J, Hafler DA, Sontag E, Wang J, Tsang JS, Day JD, Kleinstein SH, Butte AJ, Altman MC, Hammond R, Sealfon SC. Solving Immunology? Trends In Immunology 2016, 38: 116-127. PMID: 27986392, PMCID: PMC5695553, DOI: 10.1016/j.it.2016.11.006.Peer-Reviewed Original ResearchTGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage
Taylor RA, Chang CF, Goods BA, Hammond MD, Mac 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 ResearchConceptsIntracerebral 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 formThe 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
2015
Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells
Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, Hafler DA. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. Journal Of Clinical Investigation 2015, 125: 4212-4222. PMID: 26524592, PMCID: PMC4639983, DOI: 10.1172/jci81151.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntibodies, NeutralizingAutoimmunityCD4-Positive T-LymphocytesCells, CulturedCoculture TechniquesColitisCytokinesForkhead Transcription FactorsGene Expression ProfilingGenes, ReporterGraft vs Host DiseaseHeterograftsHumansImmediate-Early ProteinsInflammationInterferon-gammaLeukocytes, MononuclearMaleMiceProtein Serine-Threonine KinasesRNA InterferenceRNA, Small InterferingSodium ChlorideSodium Chloride, DietaryT-Lymphocytes, RegulatoryConceptsHigh-salt dietTreg functionIFNγ secretionCD4 effector cellsHuman Treg functionRegulatory T cellsAdoptive transfer modelAnti-IFNγ antibodyHost disease modelType 1 diabetesInduction of proinflammatoryTreg pathwayExperimental colitisXenogeneic graftEffector cellsMultiple sclerosisProinflammatory responseT cellsTregsMurine modelSuppressive activitySuppressive functionSerum/glucocorticoid-regulated kinaseAutoimmunityGlucocorticoid-regulated kinaseProspects of immune checkpoint modulators in the treatment of glioblastoma
Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nature Reviews Neurology 2015, 11: 504-514. PMID: 26260659, PMCID: PMC4782584, DOI: 10.1038/nrneurol.2015.139.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsGlioblastoma patientsMultiple immunosuppressive mechanismsMedian overall survivalImmune checkpoint modulatorsBlood-brain barrierTreatment of glioblastomaOverall survivalImmunosuppressive mechanismsAdvanced tumorsClinical benefitImmunotherapeutic agentsConventional therapyCheckpoint modulatorsLung cancerImmune systemPatientsCancerInhibitorsCurrent understandingImmunotherapyPrognosisLymphocytesTherapySodium-activated macrophages: the salt mine expands
Lucca LE, Hafler DA. Sodium-activated macrophages: the salt mine expands. Cell Research 2015, 25: 885-886. PMID: 26215700, PMCID: PMC4528060, DOI: 10.1038/cr.2015.91.Peer-Reviewed Original ResearchGenetic 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 ResearchConceptsGenetic 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 diagnosticsThymic Selection: To Thine Own Self Be True
Kitz A, Hafler DA. Thymic Selection: To Thine Own Self Be True. Immunity 2015, 42: 788-789. PMID: 25992854, DOI: 10.1016/j.immuni.2015.05.007.Peer-Reviewed Original Research
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 FactorT-Lymphocytes, RegulatoryTh17 CellsConceptsTim-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 functionDecreased 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 transcriptionRegulatory T cells in autoimmune neuroinflammation
Kleinewietfeld M, Hafler DA. Regulatory T cells in autoimmune neuroinflammation. Immunological Reviews 2014, 259: 231-244. PMID: 24712469, PMCID: PMC3990868, DOI: 10.1111/imr.12169.Peer-Reviewed Original ResearchConceptsRegulatory T cellsT cellsAutoimmune neuroinflammationMultiple sclerosisRegulatory type 1 (Tr1) cellsForkhead box protein 3Natural Treg cellsBox protein 3Experimental animal modelsT helper cell lineagesType 1 cellsTr1 cellsTreg cellsPeripheral toleranceAnimal modelsSpecific subtypesNeuroinflammationProtein 3SubtypesCell typesCell lineagesCellsTregsSclerosis