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
2017
Podoplanin is a negative regulator of Th17 inflammation
Nylander AN, Ponath GD, Axisa PP, Mubarak M, Tomayko M, Kuchroo VK, Pitt D, Hafler DA. Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2017, 2: e92321. PMID: 28878118, PMCID: PMC5621890, DOI: 10.1172/jci.insight.92321.Peer-Reviewed Original ResearchConceptsT cellsIL-17IL-17 secretionDistinct cytokine profilesInflammatory gene signatureTh17-polarizing conditionsTh17 cellsCytokine profileCell subsetsInflammatory responseSkin biopsiesMouse modelPDPN expressionMultiple organsSkin diseasesGene signatureInflammationLymphatic systemCLEC-2PDPNRecent dataDifferent subpopulationsCellsTranscriptional profilesShRNA gene
2014
Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection
Qian F, Goel G, Meng H, Wang X, You F, Devine L, Raddassi K, Garcia MN, Murray KO, Bolen CR, Gaujoux R, Shen-Orr SS, Hafler D, Fikrig E, Xavier R, Kleinstein SH, Montgomery RR. Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection. MSphere 2014, 22: 6-16. PMID: 25355795, PMCID: PMC4278927, DOI: 10.1128/cvi.00508-14.Peer-Reviewed Original ResearchConceptsWest Nile virus infectionVirus infectionMyeloid dendritic cellsMarker of susceptibilityPotential therapeutic strategySeverity of infectionSevere neurological diseaseOlder patientsAcute infectionDendritic cellsCXCL10 expressionDetectable yearsImmunity-related genesStratified cohortWNV infectionTherapeutic strategiesPathogenic mechanismsAnimal studiesNeurological diseasesDisease severityVivo infectionPredictive signatureInfectionProminent alterationsPrimary cellsSmall-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 BiologyT-Lymphocyte SubsetsTh17 CellsTranscription, 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
2007
A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies
Bradshaw EM, Orihuela A, McArdel SL, Salajegheh M, Amato AA, Hafler DA, Greenberg SA, O’Connor K. A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies. The Journal Of Immunology 2007, 178: 547-556. PMID: 17182595, DOI: 10.4049/jimmunol.178.1.547.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAmino Acid SequenceAntibody FormationAutoantigensB-Lymphocyte SubsetsFemaleGenes, Immunoglobulin Heavy ChainHumansImmunoglobulin Switch RegionImmunoglobulin Variable RegionMaleMicrodissectionMiddle AgedMolecular Sequence DataMutationMyocardiumMyositisReceptors, Antigen, B-CellSyndecan-1Transcription, GeneticConceptsInclusion body myositisLaser capture microdissectionBody myositisCapture microdissectionInflammatory myopathiesMuscle tissueInsertions/deletionsT cell-mediated diseaseGene sequencesCell-mediated diseaseGene transcriptsInflamed muscle tissueAg-specific responsesAg receptorB cell maturationPlasma cell populationPutative autoimmune disordersControl muscle tissueSignificant somatic mutationsIndividual cellsVariable region gene sequencesOligoclonal expansionInflammatory infiltrateSomatic mutationsMuscle weakness
2000
Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies
Kiefer R, Dangond F, Mueller M, Toyka KV, Hafler DA, Hartung HP. Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies. Journal Of Neurology Neurosurgery & Psychiatry 2000, 69: 362. PMID: 10945811, PMCID: PMC1737105, DOI: 10.1136/jnnp.69.3.362.Peer-Reviewed Original ResearchMeSH KeywordsB7-1 AntigenBiopsyHumansInflammationMacrophagesPeripheral Nervous System DiseasesSural NerveTranscription, GeneticUp-RegulationConceptsChronic inflammatory demyelinating polyneuropathyGuillain-Barré syndromeSural nerve biopsyPeripheral nervous systemB7-1Nerve biopsyB7-2 mRNAB7 moleculesPolymerase chain reactionB7-2Nervous systemCases of GBSNon-inflammatory control groupCostimulatory molecules B7-1B7-1 mRNANon-inflammatory controlsTh-2 phenotypeInflammatory demyelinating polyneuropathyB7-1 proteinCostimulatory molecule expressionT cell responsesEffective antigen presentationCases of neuroborreliosisHuman sural nerve biopsiesCIDP cases
1997
Variable Immortalizing Potential and Frequent Virus Latency in Blood-Derived T-Cell Clones Infected With Human T-Cell Leukemia Virus Type I
Richardson JH, Höllsberg P, Windhagen A, Child LA, Hafler DA, Lever A. Variable Immortalizing Potential and Frequent Virus Latency in Blood-Derived T-Cell Clones Infected With Human T-Cell Leukemia Virus Type I. Blood 1997, 89: 3303-3314. PMID: 9129036, DOI: 10.1182/blood.v89.9.3303.Peer-Reviewed Original ResearchConceptsT cell clonesHuman T-cell leukemia virus type IVirus type IT cellsSpontaneous proliferationFresh peripheral blood lymphocytesGag p24 productionCD4 T cellsInfected cellsPeripheral blood lymphocytesHTLV-I provirusViral mRNA expressionType IP24 productionVirus-cell interactionsIL-6Virus carriersInterleukin-6Blood lymphocytesHost cell factorsCytokine mRNAVirus latencyVirus-producing clonesHTLVMRNA expression
1996
Induction of anergy in CD8 T cells by B cell presentation of antigen.
Höllsberg P, Batra V, Dressel A, Hafler DA. Induction of anergy in CD8 T cells by B cell presentation of antigen. The Journal Of Immunology 1996, 157: 5269-76. PMID: 8955172, DOI: 10.4049/jimmunol.157.12.5269.Peer-Reviewed Original ResearchMeSH KeywordsAntigen-Presenting CellsB-LymphocytesB7-1 AntigenCD40 LigandCD8-Positive T-LymphocytesCell LineClonal AnergyCytotoxicity, ImmunologicGene ExpressionHumansImmunologic MemoryInterleukin-2Lymphocyte ActivationMembrane GlycoproteinsReceptors, Antigen, T-CellSignal TransductionTranscription, GeneticConceptsCD8 T cellsT cell clonesInduction of anergyT cellsB cellsMononuclear cellsB7-1Cell clonesAg stimulationAnergic CD8 T cellsPeptide-pulsed B cellsPeptide-pulsed target cellsCD4 T-cell clonesCD8 T cell clonesSecondary Ag challengeExogenous IL-2B7-2 costimulationB cell presentationT cell anergyIL-2 secretionNormal proliferative responseIL-2 mRNA transcriptionT cell stimulationEarly tyrosine phosphorylationAdequate costimulation
1994
Regional specificity of HTLV-I pro viral integration in the human genome
Zoubak S, Richardson JH, Rynditch A, Hollsberg P, Hafler DA, Boeri E, Lever A, Bernardi G. Regional specificity of HTLV-I pro viral integration in the human genome. Gene 1994, 143: 155-163. PMID: 8206368, DOI: 10.1016/0378-1119(94)90091-4.Peer-Reviewed Original Research
1991
Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease.
Brod SA, Benjamin D, Hafler DA. Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease. The Journal Of Immunology 1991, 147: 810-5. PMID: 1907306, DOI: 10.4049/jimmunol.147.3.810.Peer-Reviewed Original ResearchConceptsPeripheral bloodCSF of subjectsIL-5 mRNAT cell clonesIFN-gamma mRNAIL-4Inflammatory diseasesIFN-gammaIL-2Systemic inflammationT cellsTh1 T cell clonesTh2-type T cellsT cell cytokine profilesIL-2/ILDistinct T cell populationsCell clonesT cell populationsT cell expressionType T cellsTNF-alpha mRNAHuman inflammatory diseasesIL-2 mRNACytokine profileImmune compartment