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 mechanismsThe regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases
Sumida T, Cheru N, Hafler D. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nature Reviews Immunology 2024, 24: 503-517. PMID: 38374298, PMCID: PMC11216899, DOI: 10.1038/s41577-024-00994-x.Peer-Reviewed Original ResearchTreg cell dysfunctionTreg cellsAutoimmune diseasesCell dysfunctionSuppressive function of Treg cellsDifferentiation of regulatory T cellsFunction of Treg cellsDiscovery of Foxp3Foxp3-independent mechanismsTreg cell suppressionRegulatory T cellsTreg cell functionTranscription factor Foxp3Systemic lupus erythematosusRegulate immune responsesInflammatory bowel diseaseFOXP3 mutationsFoxp3-dependentSystemic autoinflammationRegulatory TIPEX syndromeCell lineage determinationT cellsTregsLupus erythematosus
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 variantsFatty Acid Metabolism and T Cells in Multiple Sclerosis
Pompura SL, Hafler DA, Dominguez-Villar M. Fatty Acid Metabolism and T Cells in Multiple Sclerosis. Frontiers In Immunology 2022, 13: 869197. PMID: 35603182, PMCID: PMC9116144, DOI: 10.3389/fimmu.2022.869197.Peer-Reviewed Original ResearchConceptsT cell functionT cellsMultiple sclerosisSpecific lipid speciesEffector T cellsRegulatory T cellsCell functionT helper subsetsMetabolic programsT cell activationT cell transitionLipid speciesFatty acid metabolismTh subsetsHelper subsetsEffector stateBody of evidenceCell activationDisease settingsDisease statesFunctional phenotypeOrganismal levelAcid metabolismMetabolic remodelingNutrient availability
2021
Oleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis
Pompura SL, Wagner A, Kitz A, Laperche J, Yosef N, Dominguez-Villar M, Hafler D. Oleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis. Journal Of Clinical Investigation 2021, 131 PMID: 33170805, PMCID: PMC7810477, DOI: 10.1172/jci138519.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAdipose tissueFoxp3 regulatory T cellsExpression of Foxp3Regulatory T cellsTreg suppressive functionProinflammatory arachidonic acidHuman adipose tissuePhosphorylation of STAT5Treg homeostasisFatty acidsPeripheral bloodTissue residencyHealthy donorsInflammatory signalsT cellsTregsFree fatty acidsSuppressive functionArachidonic acidPatientsOleic acidOxidative phosphorylationTranscriptomic programsFoxp3
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-cateninIFNFingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo
Dominguez-Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Hafler DA. Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo. Journal Of Autoimmunity 2018, 96: 40-49. PMID: 30122421, PMCID: PMC7882197, DOI: 10.1016/j.jaut.2018.08.002.Peer-Reviewed Original ResearchConceptsT cellsMultiple sclerosisT cell effector phenotypeRelapsing-remitting multiple sclerosisRegulatory T cell populationTh1-like phenotypeRegulatory T cellsPro-inflammatory cytokinesT-cell phenotypeT cell populationsExpression of Th1Immune cell functionRegulatory T cell plasticityT cell plasticityCentral nervous systemExpression of markersCell migratory capacityImportant immunomodulatory functionsExcessive Th1Fingolimod treatmentExhaustion markersTh17 cytokinesEffector phenotypeLymph nodesSerum levelsRegulatory 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
2016
Production of Proinflammatory Cytokines by Monocytes in Liver-Transplanted Recipients with De Novo Autoimmune Hepatitis Is Enhanced and Induces TH1-like Regulatory T Cells
Arterbery AS, Osafo-Addo A, Avitzur Y, Ciarleglio M, Deng Y, Lobritto SJ, Martinez M, Hafler DA, Kleinewietfeld M, Ekong UD. Production of Proinflammatory Cytokines by Monocytes in Liver-Transplanted Recipients with De Novo Autoimmune Hepatitis Is Enhanced and Induces TH1-like Regulatory T Cells. The Journal Of Immunology 2016, 196: 4040-4051. PMID: 27183637, PMCID: PMC4874532, DOI: 10.4049/jimmunol.1502276.Peer-Reviewed Original ResearchConceptsRegulatory T cellsIL-12IL-6T cellsSuppressive functionDe novo autoimmune hepatitisHuman regulatory T cellsNovo autoimmune hepatitisProinflammatory IL-12Th17 effector cellsTregs of patientsDifferentiation of TregsIL-17 cytokinesBlockade of IFNMonocyte/macrophage cellsLiver of subjectsAutoimmune hepatitisDominant cytokineProinflammatory IFNTH1-likeIL-17Treg phenotypeTreg dysfunctionEffector cellsInflammatory milieuPD-1 marks dysfunctional regulatory T cells in malignant gliomas
Lowther DE, Goods BA, Lucca LE, Lerner BA, Raddassi K, van Dijk D, Hernandez AL, Duan X, Gunel M, Coric V, Krishnaswamy S, Love JC, Hafler DA. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 2016, 1: e85935. PMID: 27182555, PMCID: PMC4864991, DOI: 10.1172/jci.insight.85935.Peer-Reviewed Original ResearchTumor-infiltrating TregsPD-1IFN-γ productionGlioblastoma multiformeT cellsImmune responseHealthy subjectsDysfunctional regulatory T cellsHigh PD-1 expressionCell death protein 1PD-1-blocking antibodiesPD-1 expressionEffector T cellsRegulatory T cellsDeath protein 1Antitumoral immune responseImmune checkpoint receptorsProduction of IFNExhausted phenotypeExhaustion signaturesCheckpoint receptorsHuman TregsTumor infiltratesFunctional statusMalignant gliomas
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 kinase
2014
Genetic and epigenetic fine mapping of causal autoimmune disease variants
Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, Shoresh N, Whitton H, Ryan RJ, Shishkin AA, Hatan M, Carrasco-Alfonso MJ, Mayer D, Luckey CJ, Patsopoulos NA, De Jager PL, Kuchroo VK, Epstein CB, Daly MJ, Hafler DA, Bernstein BE. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 2014, 518: 337-343. PMID: 25363779, PMCID: PMC4336207, DOI: 10.1038/nature13835.Peer-Reviewed Original ResearchConceptsCausal variantsAutoimmune diseasesT cellsRegulatory T cellsNon-coding risk variantsT cell subsetsEnhancer-associated RNAsGenome-wide association studiesPrimary immune cellsCandidate causal variantsGene regulatory modelsImmune cellsImmune stimulationB cellsGene activationFine mappingTranscription factorsMaster regulatorHistone acetylationImmune differentiationSequence determinantsGene expressionAssociation studiesDiseaseHuman diseasesEnhanced 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 functionRegulatory 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 lineagesCellsTregsSclerosisChapter 52 Multiple Sclerosis
Hernandez A, O’Connor K, Hafler D. Chapter 52 Multiple Sclerosis. 2014, 735-756. DOI: 10.1016/b978-0-12-384929-8.00052-6.ChaptersMultiple sclerosisT cellsCell subsetsInflammatory autoimmune diseaseRegulatory T cellsT cell subsetsCNS white matterB cell subsetsImmune dysregulationTh1 subsetAutoimmune diseasesHumoral responseDisease evolutionInfectious agentsGenetic susceptibility lociProgressive neurodegenerationWhite matterCurrent diseaseGenetic riskDiseasePotential roleSclerosisSusceptible hostsTherapyPutative role
2013
The plasticity of human Treg and Th17 cells and its role in autoimmunity
Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Seminars In Immunology 2013, 25: 305-312. PMID: 24211039, PMCID: PMC3905679, DOI: 10.1016/j.smim.2013.10.009.Peer-Reviewed Original ResearchConceptsTh17 cellsT cellsMultiple sclerosisAutoimmune diseasesImmune systemPlasticity of TregsEffector T cellsRegulatory T cellsEffector cell populationsHuman autoimmune diseasesT cell subpopulationsT helper cellsParticular multiple sclerosisT cell plasticityHigh gradeInnate immune systemAdaptive immune systemStrength of stimulationT cell developmentHuman TregsHelper cellsImmune responseImmune reactionsNaive cellsTregsRegulatory T Cells in MS
Gawlik B, Hafler D. Regulatory T Cells in MS. 2013, 27-47. DOI: 10.1007/978-1-4614-7953-6_2.Peer-Reviewed Original ResearchRegulatory T cellsAutoreactive T cellsT cellsCentral nervous systemMultiple sclerosisTreg cellsHealthy individualsPathogenic autoreactive T cellsMultifocal demyelinating diseaseDemyelinating diseaseCNS lesionsMS patientsAutoimmune responseAutoimmune diseasesPeripheral bloodImmune homeostasisImmune responseNervous systemSusceptible individualsProgressive neurodegenerationDiseaseKey regulatorCellsIndividualsHigher numberMicrobial Reprogramming Inhibits Western Diet-Associated Obesity
Poutahidis T, Kleinewietfeld M, Smillie C, Levkovich T, Perrotta A, Bhela S, Varian BJ, Ibrahim YM, Lakritz JR, Kearney SM, Chatzigiagkos A, Hafler DA, Alm EJ, Erdman SE. Microbial Reprogramming Inhibits Western Diet-Associated Obesity. PLOS ONE 2013, 8: e68596. PMID: 23874682, PMCID: PMC3707834, DOI: 10.1371/journal.pone.0068596.Peer-Reviewed Original ResearchConceptsAge-associated weight gainWeight gainT cellsFast foodAd libitum caloric intakeActive immune toleranceImmune cell profilesRegulatory T cellsT cell balanceRecent epidemiological studiesLikelihood of obesityNaïve recipient animalsGut microbial ecologyT helperImmune toleranceBaseline dietWeight managementCaloric intakePopulation-based approachMouse modelCell balanceEpidemiological studiesRecipient animalsAnimal modelsAbdominal fat