2023
BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS
Lu B, Lucca L, DiStasio M, Liu Y, Pham G, Buitrago-Pocasangre N, Arnal-Estape A, Moliterno J, Chiang V, Omuro A, Hafler D. BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS. Neuro-Oncology Advances 2023, 5: iii4-iii4. PMCID: PMC10402449, DOI: 10.1093/noajnl/vdad070.014.Peer-Reviewed Original ResearchT cell populationsT cell functionT cellsHigh-grade gliomasBrain metastasesHuman brain tumorsImmune cellsBrain tumorsNon-small cell lung cancer brain metastasesB cellsAnti-PD-1 therapy responseCell lung cancer brain metastasesLung cancer brain metastasesProductive antitumor immune responsesFollicular helper T cellsT-cell receptor sequencingTumor-infiltrating T cellsAntitumor T-cell functionCancer brain metastasesCo-inhibitory receptorsAntitumor immune responseCell receptor sequencingLonger overall survivalCell functionTertiary lymphoid structuresCommon genetic factors among autoimmune diseases
Harroud A, Hafler D. Common genetic factors among autoimmune diseases. Science 2023, 380: 485-490. PMID: 37141355, DOI: 10.1126/science.adg2992.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesMultimodal genomic dataEvolutionary originDisease geneticsPolygenic basisPrecise geneSelection pressureGenomic dataMolecular consequencesAssociation studiesGenetic studiesFunctional experimentsGenetic effectsRisk variantsCommon genetic factorsAncient populationsCurrent understandingPotential therapeutic implicationsGenetic factorsKey immune cellsGenesGeneticsWidespread sharingImmune cellsValuable insights
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 variantsBasic principles of neuroimmunology
Yoshida TM, Wang A, Hafler DA. Basic principles of neuroimmunology. Seminars In Immunopathology 2022, 44: 685-695. PMID: 35732977, DOI: 10.1007/s00281-022-00951-7.Peer-Reviewed Original ResearchConceptsNeuro-immune interactionsCentral nervous systemImmune privilegeCerebrospinal fluidCNS-resident immune cellsImmune-derived cytokinesResident T cellsImmune cell infiltrationImmune-privileged organMeningeal lymphatic systemIntroduction of antigenImmune compartmentNeuroinflammatory diseasesNeurological functionCNS homeostasisCell infiltrationHarmful inflammationImmune cellsPeripheral organsT cellsImmune responseLeukocyte traffickingNervous systemImmune systemLymphatic system
2021
Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells
Jiang R, Meng H, Raddassi K, Fleming I, Hoehn KB, Dardick KR, Belperron AA, Montgomery RR, Shalek AK, Hafler DA, Kleinstein SH, Bockenstedt LK. Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells. JCI Insight 2021, 6: e148035. PMID: 34061047, PMCID: PMC8262471, DOI: 10.1172/jci.insight.148035.Peer-Reviewed Original ResearchConceptsMemory B cellsErythema migransB cellsEM lesionsIgM memory B cellsLyme diseaseB-cell receptor sequencingSkin infection siteCell receptor sequencingEarly Lyme diseaseLocal antigen presentationSkin immune responsesB cell populationsSingle-cell immunophenotypingMHC class II genesUninvolved skinImmune cellsSpirochetal infectionAntigen presentationCell immunophenotypingT cellsImmune responseIsotype usageAntibody productionInitial signsClinical Significance of PDCD4 in Melanoma by Subcellular Expression and in Tumor-Associated Immune Cells
Tran TT, Rane CK, Zito CR, Weiss SA, Jessel S, Lucca L, Lu BY, Oria VO, Adeniran A, Chiang VL, Omay SB, Hafler DA, Kluger HM, Jilaveanu LB. Clinical Significance of PDCD4 in Melanoma by Subcellular Expression and in Tumor-Associated Immune Cells. Cancers 2021, 13: 1049. PMID: 33801444, PMCID: PMC7958624, DOI: 10.3390/cancers13051049.Peer-Reviewed Original ResearchPDCD4 expressionImproved survivalTumor-Associated Immune CellsTumor microenvironmentNeoplastic progressionBrain metastasis outcomesExtracranial metastatic diseaseMelanoma brain metastasesNatural killer cellsBrain metastasis samplesImmune cell infiltrationImmune cell subsetsMultiple tissue microarraysExpression of PDCD4Brain metastasesMetastatic diseaseClinical outcomesKiller cellsClinicopathological variablesIntracranial metastasesCell subsetsCell infiltrationCell death 4Immune cellsPrimary melanoma
2019
Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
Patsopoulos N, Baranzini S, Santaniello A, Shoostari P, Cotsapas C, Wong G, Beecham A, James T, Replogle J, Vlachos I, McCabe C, Pers T, Brandes A, White C, Keenan B, Cimpean M, Winn P, Panteliadis I, Robbins A, Andlauer T, Zarzycki O, Dubois B, Goris A, Søndergaard H, Sellebjerg F, Sorensen P, Ullum H, Thørner L, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusic S, Berthele A, Pongratz V, Buck D, Gasperi C, Graetz C, Grummel V, Hemmer B, Hoshi M, Knier B, Korn T, Lill C, Luessi F, Mühlau M, Zipp F, Dardiotis E, Agliardi C, Amoroso A, Barizzone N, Benedetti M, Bernardinelli L, Cavalla P, Clarelli F, Comi G, Cusi D, Esposito F, Ferrè L, Galimberti D, Guaschino C, Leone M, Martinelli V, Moiola L, Salvetti M, Sorosina M, Vecchio D, Zauli A, Santoro S, Mancini N, Zuccalà M, Mescheriakova J, van Duijn C, Bos S, Celius E, Spurkland A, Comabella M, Montalban X, Alfredsson L, Bomfim I, Gomez-Cabrero D, Hillert J, Jagodic M, Lindén M, Piehl F, Jelčić I, Martin R, Sospedra M, Baker A, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Molyneux P, Neville M, Thorpe J, Bradshaw E, Caillier S, Calabresi P, Cree B, Cross A, Davis M, de Bakker P, Delgado S, Dembele M, Edwards K, Fitzgerald K, Frohlich I, Gourraud P, Haines J, Hakonarson H, Kimbrough D, Isobe N, Konidari I, Lathi E, Lee M, Li T, An D, Zimmer A, Madireddy L, Manrique C, Mitrovic M, Olah M, Patrick E, Pericak-Vance M, Piccio L, Schaefer C, Weiner H, Lage K, Compston A, Hafler D, Harbo H, Hauser S, Stewart G, D’Alfonso S, Hadjigeorgiou G, Taylor B, Barcellos L, Booth D, Hintzen R, Kockum I, Martinelli-Boneschi F, McCauley J, Oksenberg J, Oturai A, Sawcer S, Ivinson A, Olsson T, De Jager P. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019, 365 PMID: 31604244, PMCID: PMC7241648, DOI: 10.1126/science.aav7188.Peer-Reviewed Original ResearchMeSH KeywordsCase-Control StudiesCell Cycle ProteinsChromosome MappingChromosomes, Human, XGene FrequencyGenetic LociGenome-Wide Association StudyGenomicsGTPase-Activating ProteinsHumansInheritance PatternsMajor Histocompatibility ComplexMicrogliaMultiple SclerosisPolymorphism, Single NucleotideQuantitative Trait LociRNA-SeqTranscriptomeConceptsMajor histocompatibility complexMultiple sclerosisImmune cellsBrain-resident immune cellsPeripheral immune cellsPeripheral immune responseCentral nervous systemExtended major histocompatibility complexAutoimmune processControl subjectsHuman microgliaImmune responseNervous systemImmune systemHistocompatibility complexPutative susceptibility genesMicrogliaX variantGenetic architectureSusceptibility genesGenomic mapGenetic dataExpression profilesM geneSusceptibility variantsMultiple sclerosis enters a grey area
Pappalardo JL, Hafler DA. Multiple sclerosis enters a grey area. Nature 2019, 566: 465-466. PMID: 30809050, DOI: 10.1038/d41586-019-00563-6.Peer-Reviewed Original Research
2018
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Ponath G, Lincoln MR, Levine-Ritterman M, Park C, Dahlawi S, Mubarak M, Sumida T, Airas L, Zhang S, Isitan C, Nguyen TD, Raine CS, Hafler DA, Pitt D. Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nature Communications 2018, 9: 5337. PMID: 30559390, PMCID: PMC6297228, DOI: 10.1038/s41467-018-07785-8.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAstrocyte responseRisk variantsLocal autoimmune inflammationPeripheral immune cellsCentral nervous system cellsPeripheral immune systemCultured human astrocytesNervous system cellsNF-κB signalingCNS accessDysfunctional lymphocytesAstroglial functionAutoimmune inflammationLymphocytic infiltrateLymphocyte recruitmentImmune cellsGenetic risk allelesGenetic risk variantsMS lesionsMS susceptibilityHuman astrocytesLesion sizeImmune systemSystem cells
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 diseases
2011
An Innate Role for IL-17
Dominguez-Villar M, Hafler DA. An Innate Role for IL-17. Science 2011, 332: 47-48. PMID: 21454778, DOI: 10.1126/science.1205311.Peer-Reviewed Original ResearchConceptsImmune responseImmune dysregulation polyendocrinopathyAbnormal immune responseRegulatory immune cellsRegulatory T cellsHuman autoimmune disordersCytokine interleukin-17Normal immune responseTranscription factor Foxp3IL-17Interleukin-17Autoimmune disordersAutoimmune diseasesImmune cellsImmune system processFOXP3 geneFactor Foxp3T cellsImmune systemFungal infectionsGenetic mutationsHuman genetic mutationsCytokinesInfectionCell types
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 factor
2007
Allelic variant in CTLA4 alters T cell phosphorylation patterns
Maier LM, Anderson DE, De Jager PL, Wicker LS, Hafler DA. Allelic variant in CTLA4 alters T cell phosphorylation patterns. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 18607-18612. PMID: 18000051, PMCID: PMC2141824, DOI: 10.1073/pnas.0706409104.Peer-Reviewed Original ResearchConceptsT cell antigen receptorAllelic variationMemory T cellsAutoimmune diseasesCell antigen receptorT cell signalingT cellsFunctional effectsDisease susceptibility allelesCell signalingPhosphorylation patternPhosphorylation levelsSusceptibility variantsTCR stimulationAllelic variantsHuman immune cellsAntigen receptorGenesImmune cellsHealthy individualsCTLA4 geneCellsSpecific mAbsCTLA4DiseasePromotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells
Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA. Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells. Science 2007, 318: 1141-1143. PMID: 18006747, DOI: 10.1126/science.1148536.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesCD11b AntigenCentral Nervous System NeoplasmsDendritic CellsEncephalomyelitis, Autoimmune, ExperimentalGalectinsGlioblastomaHepatitis A Virus Cellular Receptor 2HumansImmunity, InnateInflammation MediatorsLipopolysaccharidesMacrophagesMembrane ProteinsMiceMicrogliaMultiple SclerosisRatsReceptors, ImmunologicReceptors, VirusSignal TransductionTh1 CellsT-LymphocytesToll-Like ReceptorsConceptsImmune receptor Tim-3Tim-3Immune cellsT helper 1 cellsAdaptive immune cellsInnate immune cellsToll-like receptorsInduced Immune ResponsesInnate immune systemTh1 immunityDendritic cellsTissue inflammationInflammatory conditionsT cellsImmune responseImmune systemImportant mediatorAntibody agonistsInflammationCell typesLatter findingNumerous pathwaysCellsDifferential expressionCD4
2005
Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope
Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005, 435: 224-228. PMID: 15889096, DOI: 10.1038/nature03625.Peer-Reviewed Original ResearchConceptsWhite blood cellsAutoimmune diabetesLymph nodesType 1 diabetic subjectsPancreatic lymph nodesAntigen-specific therapyExpanded T cellsIslet cell transplantationType 1 diabetesPossible clinical relevanceStandard animal modelPrimary autoantigenNOD miceDiabetic subjectsImmune therapyMultiple sclerosisChildhood diabetesInsulin-producing cellsSpecific therapyImmune cellsT cellsT lymphocytesInsulin epitopesAnimal modelsClinical relevance
1998
Differential Display Cloning of a Novel Human Histone Deacetylase (HDAC3) cDNA from PHA-Activated Immune Cells
Dangond F, Hafler D, Tong J, Randall J, Kojima R, Utku N, Gullans S. Differential Display Cloning of a Novel Human Histone Deacetylase (HDAC3) cDNA from PHA-Activated Immune Cells. Biochemical And Biophysical Research Communications 1998, 242: 648-652. PMID: 9464271, DOI: 10.1006/bbrc.1997.8033.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBlotting, NorthernCD3 ComplexCell CycleCloning, MolecularDNAFlow CytometryGene Expression Regulation, EnzymologicGranulocyte-Macrophage Colony-Stimulating FactorHistone DeacetylasesHumansMolecular Sequence DataPhylogenyPhytohemagglutininsRNA, MessengerSequence AlignmentSequence Analysis, DNAT-LymphocytesTransfectionTumor Cells, CulturedConceptsPeripheral blood mononuclear cellsBlock T cell proliferationEffects of HDACsBlood mononuclear cellsT cell proliferationT cell clonesG2/M cell accumulationNon-immune tissuesTHP-1 cellsHDAC mRNAsPBMC levelsDifferential display cloningMononuclear cellsIL-4Immune cellsIFN-gammaAlpha CD3Histone acetyltransferasesCell accumulationHDAC3 mRNAHDAC inhibitorsHistone deacetylase assayCell clonesCell cycle progressionFunctional activity