2016
AKT isoforms modulate Th1‐like Treg generation and function in human autoimmune disease
Kitz A, de Marcken M, Gautron AS, Mitrovic M, Hafler DA, Dominguez-Villar M. AKT isoforms modulate Th1‐like Treg generation and function in human autoimmune disease. EMBO Reports 2016, 17: 1169-1183. PMID: 27312110, PMCID: PMC4967959, DOI: 10.15252/embr.201541905.Peer-Reviewed Original ResearchMeSH KeywordsAutoimmune DiseasesBiomarkersCell DifferentiationCytokinesForkhead Transcription FactorsGene Expression ProfilingGene SilencingHumansImmunomodulationInterferon-gammaPhenotypePhosphatidylinositol 3-KinasesProtein IsoformsProto-Oncogene Proteins c-aktSignal TransductionT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryTranscriptomeConceptsAutoimmune diseasesIFNγ secretionHuman TregsGenome-wide gene expression approachUntreated relapsing-remitting MS patientsRelapsing-remitting MS patientsImmune suppressive functionHuman autoimmune diseasesT helper 1Inflammatory cytokines IFNγTreg suppressor functionNovel treatment paradigmEffector phenotypeMS patientsTreg generationCytokines IFNγHelper 1Multiple sclerosisTreatment paradigmSuppressive functionTregsVivo modelDiseaseSecretionSuppressor function
2014
B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes
Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O'Connor KC. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Science Translational Medicine 2014, 6: 248ra107. PMID: 25100741, PMCID: PMC4388137, DOI: 10.1126/scitranslmed.3008879.Peer-Reviewed Original ResearchConceptsCervical lymph nodesCentral nervous systemB cellsCerebrospinal fluidLymph nodesMultiple sclerosisLymphoid tissueCNS of patientsCNS B cellsAntigen-experienced B cellsMultiple sclerosis brainSecondary lymphoid tissuesB cell compartmentB cell trafficB cell maturationImmunomodulatory therapyImmune infiltratesPeripheral bloodInflammatory diseasesLymphocyte transmigrationPeripheral tissuesNervous systemMembers of clonesCell maturationCell trafficEnhanced 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 functionSmall-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 BiologyTh17 CellsT-Lymphocyte SubsetsTranscription, 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
2012
Induction and molecular signature of pathogenic TH17 cells
Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic TH17 cells. Nature Immunology 2012, 13: 991-999. PMID: 22961052, PMCID: PMC3459594, DOI: 10.1038/ni.2416.Peer-Reviewed Original Research
2011
CD2 Costimulation Reveals Defective Activity by Human CD4+CD25hi Regulatory Cells in Patients with Multiple Sclerosis
Baecher-Allan CM, Costantino CM, Cvetanovich GL, Ashley CW, Beriou G, Dominguez-Villar M, Hafler DA. CD2 Costimulation Reveals Defective Activity by Human CD4+CD25hi Regulatory Cells in Patients with Multiple Sclerosis. The Journal Of Immunology 2011, 186: 3317-3326. PMID: 21300823, PMCID: PMC4467560, DOI: 10.4049/jimmunol.1002502.Peer-Reviewed Original ResearchMeSH KeywordsAdultCD2 AntigensCD4 AntigensCell DifferentiationCells, CulturedCoculture TechniquesFetal BloodForkhead Transcription FactorsHumansInfant, NewbornInterleukin-2 Receptor alpha SubunitInterleukin-7 Receptor alpha SubunitLymphocyte ActivationMiddle AgedMultiple SclerosisSignal TransductionT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryYoung AdultConceptsMultiple sclerosisIL-17Suppressive capacityDR cellsRegulatory T cell populationEffector T cellsExpression of CD127T cell populationsMechanism of actionTreg populationRegulatory cellsIL-10Effector cellsHLA-DREffector subsetsHuman TregsCD2 costimulationMemory TregsT cellsTregsAdult bloodLow expressionSclerosisPatientsCD127
2010
FOXP3+ regulatory T cells in the human immune system
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature Reviews Immunology 2010, 10: 490-500. PMID: 20559327, DOI: 10.1038/nri2785.Peer-Reviewed Original ResearchConceptsForkhead box P3Human Treg cellsTreg cellsT cellsKey PointsRegulatory T (TReg) cellsTreg cell-based therapyAntitumour immune responseRegulatory T cellsExpression of CD45RAPromising therapeutic perspectiveHuman immune systemAutoimmune pathogenesisDominant toleranceBox P3HLA-DRCell-based therapiesAutoimmune diseasesImmune homeostasisImmune responseImmune diseasesSuppressive functionPotent mediatorCancer growthImmune systemTherapeutic perspectives
2009
Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells
Bradshaw EM, Raddassi K, Elyaman W, Orban T, Gottlieb PA, Kent SC, Hafler DA. Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells. The Journal Of Immunology 2009, 183: 4432-4439. PMID: 19748982, PMCID: PMC2770506, DOI: 10.4049/jimmunol.0900576.Peer-Reviewed Original ResearchConceptsT cellsT1D subjectsImmune systemIL-17-secreting cellsIL-17-secreting T cellsProinflammatory cytokines IL-1betaProinflammatory T cellsEffector T cellsMemory T cellsLong-term patientsHealthy control subjectsCytokines IL-1betaIL-1R antagonistType 1 diabetesInnate immune systemAdaptive immune systemTh1/T1D patientsAutoimmune diseasesIL-6Control subjectsIL-1betaHealthy controlsMonocytesType 1
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 ResearchTIM-4 Expressed on APCs Induces T Cell Expansion and Survival
Rodriguez-Manzanet R, Meyers JH, Balasubramanian S, Slavik J, Kassam N, Dardalhon V, Greenfield EA, Anderson AC, Sobel RA, Hafler DA, Strom TB, Kuchroo VK. TIM-4 Expressed on APCs Induces T Cell Expansion and Survival. The Journal Of Immunology 2008, 180: 4706-4713. PMID: 18354194, PMCID: PMC2948965, DOI: 10.4049/jimmunol.180.7.4706.Peer-Reviewed Original Research
2007
Abnormal Tr1 differentiation in multiple sclerosis
Astier AL, Hafler DA. Abnormal Tr1 differentiation in multiple sclerosis. Journal Of Neuroimmunology 2007, 191: 70-78. PMID: 17936368, PMCID: PMC2200628, DOI: 10.1016/j.jneuroim.2007.09.018.Peer-Reviewed Original ResearchConceptsMultiple sclerosisCentral nervous systemRegulatory T cell defectsInduction of TregsInflammatory demyelinating diseaseIL-10 secretionRegulatory T cellsHuman autoimmune diseasesT cell defectsContext of autoimmunityHigh TregTr1 differentiationTreg activityDemyelinating diseaseTreg cellsImmunosuppressive roleAutoimmune diseasesT cellsNervous systemAltered functionCell defectsSuch diseasesDiseaseTregsSclerosis
2001
Immune Tolerance and the Nervous System
Anderson D, Hafler D. Immune Tolerance and the Nervous System. Advances In Experimental Medicine And Biology 2001, 490: 79-98. PMID: 11505978, DOI: 10.1007/978-1-4615-1243-1_9.Peer-Reviewed Original ResearchConceptsT cellsB cellsInnate immunityForeign microbial antigensPrior viral infectionSpecific immune responseClass I moleculesNK cellsImmune toleranceMicrobial antigensImmune responseViral infectionNervous systemInfectious agentsSecondary exposureImmune systemInfectious virusParticular antigenSpecific receptorsTumor cellsAntigenI moleculesInfectionInnate mechanismsImmunity
1998
T helper cell differentiation in multiple sclerosis and autoimmunity
Martin R, Ruddle N, Reingold S, Hafler D. T helper cell differentiation in multiple sclerosis and autoimmunity. Trends In Immunology 1998, 19: 495-498. PMID: 9818541, DOI: 10.1016/s0167-5699(98)01345-0.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmunityCell DifferentiationCytokinesHumansMultiple SclerosisT-Lymphocyte SubsetsT-Lymphocytes, Helper-Inducer
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 Cells