2024
Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring
Sun J, Esplugues E, Bort A, Cardelo M, Ruz-Maldonado I, Fernández-Tussy P, Wong C, Wang H, Ojima I, Kaczocha M, Perry R, Suárez Y, Fernández-Hernando C. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring. Nature Metabolism 2024, 6: 741-763. PMID: 38664583, DOI: 10.1038/s42255-024-01019-6.Peer-Reviewed Original ResearchConceptsFatty acid binding protein 5Tumor-associated macrophagesHepatocellular carcinomaImmunosuppressive phenotype of tumor-associated macrophagesIncreased CD8+ T cell activationCD8+ T cell activationPhenotype of tumor-associated macrophagesPro-inflammatory tumor microenvironmentCo-stimulatory molecules CD80T cell activationHepatocellular carcinoma burdenTransformation of hepatocytesBinding protein 5Potential therapeutic approachImmunosuppressive phenotypeTumor microenvironmentFerroptosis-induced cell deathMale miceEnhanced ferroptosisTherapeutic approachesPharmacological inhibitionGenetic ablationIncreased expressionSingle-cell atlasAnalysis of transformed cells
2020
The induction and function of the anti-inflammatory fate of TH17 cells
Xu H, Agalioti T, Zhao J, Steglich B, Wahib R, Vesely MCA, Bielecki P, Bailis W, Jackson R, Perez D, Izbicki J, Licona-Limón P, Kaartinen V, Geginat J, Esplugues E, Tolosa E, Huber S, Flavell RA, Gagliani N. The induction and function of the anti-inflammatory fate of TH17 cells. Nature Communications 2020, 11: 3334. PMID: 32620760, PMCID: PMC7335205, DOI: 10.1038/s41467-020-17097-5.Peer-Reviewed Original Research
2019
Effector TH17 Cells Give Rise to Long-Lived TRM Cells that Are Essential for an Immediate Response against Bacterial Infection
Vesely M, Pallis P, Bielecki P, Low JS, Zhao J, Harman CCD, Kroehling L, Jackson R, Bailis W, Licona-Limón P, Xu H, Iijima N, Pillai PS, Kaplan DH, Weaver CT, Kluger Y, Kowalczyk MS, Iwasaki A, Pereira JP, Esplugues E, Gagliani N, Flavell RA. Effector TH17 Cells Give Rise to Long-Lived TRM Cells that Are Essential for an Immediate Response against Bacterial Infection. Cell 2019, 178: 1176-1188.e15. PMID: 31442406, PMCID: PMC7057720, DOI: 10.1016/j.cell.2019.07.032.Peer-Reviewed Original ResearchConceptsCD4 TTissue-resident memory T cellsBacterial infectionsResident memory T cellsFunction of airwayLife-long protectionEffector memory TMemory T cellsTh17 cellsTRM cellsΓδ TEffector cellsMemory TBacterial clearanceT cellsIL-7Adaptive immunityMouse modelMemory responsesVaccine designHost defenseLymphatic endothelial cellsDepletion studiesEndothelial cellsCellular origin
2018
Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression
Calcinotto A, Brevi A, Chesi M, Ferrarese R, Garcia Perez L, Grioni M, Kumar S, Garbitt VM, Sharik ME, Henderson KJ, Tonon G, Tomura M, Miwa Y, Esplugues E, Flavell RA, Huber S, Canducci F, Rajkumar VS, Bergsagel PL, Bellone M. Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression. Nature Communications 2018, 9: 4832. PMID: 30510245, PMCID: PMC6277390, DOI: 10.1038/s41467-018-07305-8.Peer-Reviewed Original ResearchConceptsIL-17Multiple myelomaTh17 cellsDisease progressionBone marrowInterleukin-17-producing cellsFaster disease progressionMultiple myeloma progressionExtramucosal tumorsMM patientsAvailable therapiesIL-17RAIL-5Myeloma progressionPlasma cellsGut microbiotaCommensal bacteriaInnate immunityIntestinal microbesMurine plasma cellsPrevotella heparinolyticaEosinophilsMiceProgressionSTAT3 phosphorylation
2017
Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development
Yu H, Gagliani N, Ishigame H, Huber S, Zhu S, Esplugues E, Herold KC, Wen L, Flavell RA. Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 10443-10448. PMID: 28894001, PMCID: PMC5625908, DOI: 10.1073/pnas.1705599114.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsCell DifferentiationCell MovementCell ProliferationCell- and Tissue-Based TherapyDiabetes Mellitus, Type 1DysbiosisFemaleGastrointestinal MicrobiomeImmune ToleranceInterleukin-10IntestinesMiceMice, Inbred NODMice, KnockoutReceptors, CCR4Receptors, CCR5Receptors, CCR7T-Lymphocytes, RegulatoryConceptsRegulatory T cellsTr1 cellsT cellsIL-10-producing type 1 regulatory T cellsType 1 regulatory T cellsAntigen-specific Tr1 cellsGut-associated lymphoid tissueDouble reporter miceDiabetogenic T cellsEffector T cellsDevelopment of diabetesT cells migrateIL-10 signalingType 1 diabetes managementIL-10R.NOD miceIL-10Diabetes incidenceDiabetes developmentAutoimmune diseasesTCR transgenicTh1 cellsLymphoid tissueChemokine receptorsPreclinical modelsTH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine
Pascual-Reguant A, Bayat Sarmadi J, Baumann C, Noster R, Cirera-Salinas D, Curato C, Pelczar P, Huber S, Zielinski CE, Löhning M, Hauser AE, Esplugues E. TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine. Mucosal Immunology 2017, 10: 1431-1442. PMID: 28198366, DOI: 10.1038/mi.2017.5.Peer-Reviewed Original ResearchConceptsPro-inflammatory TH17 cellsIntestinal epithelial cellsTh17 cellsSmall intestineIL-33IL-33/ST2 axisPro-inflammatory T cellsAlarmin IL-33Alarmin interleukin-33IL-33 receptorPro-inflammatory cytokinesAbsence of ST2Beneficial host responseIL-10Interleukin-33Autoimmune diseasesTissue inflammationInflammatory responseImmunosuppressive propertiesT cellsImmune responseInflamed tissuesHost responseImmune systemRegulatory phenotypeIL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo
Brockmann L, Gagliani N, Steglich B, Giannou AD, Kempski J, Pelczar P, Geffken M, Mfarrej B, Huber F, Herkel J, Wan YY, Esplugues E, Battaglia M, Krebs CF, Flavell RA, Huber S. IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo. The Journal Of Immunology 2017, 198: 1130-1141. PMID: 28003377, PMCID: PMC5263184, DOI: 10.4049/jimmunol.1601045.Peer-Reviewed Original ResearchConceptsIL-10 receptor signalingCell regulatory activityIL-10Receptor signalingIL-10 receptor expressionRegulatory type 1 (Tr1) cellsInflammatory bowel disease modelCell therapyInflammatory bowel diseaseIL-10 productionIL-10 receptorMurine inflammatory bowel disease modelT-cell therapyType 1 cellsBowel diseaseCell-based therapiesIL-10RαClinical trialsReceptor expressionIntestinal homeostasisSuppressive activityReporter miceTransgenic miceTherapyRegulatory activity
2016
TFH cells progressively differentiate to regulate the germinal center response
Weinstein JS, Herman EI, Lainez B, Licona-Limón P, Esplugues E, Flavell R, Craft J. TFH cells progressively differentiate to regulate the germinal center response. Nature Immunology 2016, 17: 1197-1205. PMID: 27573866, PMCID: PMC5030190, DOI: 10.1038/ni.3554.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody AffinityB-LymphocytesCD4 AntigensCell CommunicationCell DifferentiationCells, CulturedGene Expression RegulationGerminal CenterHumansInterleukin-4InterleukinsMiceMice, Inbred C57BLMice, Mutant StrainsMutationNippostrongylusPositive Regulatory Domain I-Binding Factor 1Strongylida InfectionsT-Lymphocytes, Helper-InducerTranscription FactorsApoptosis in response to microbial infection induces autoreactive TH17 cells
Campisi L, Barbet G, Ding Y, Esplugues E, Flavell RA, Blander JM. Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nature Immunology 2016, 17: 1084-1092. PMID: 27455420, PMCID: PMC5079524, DOI: 10.1038/ni.3512.Peer-Reviewed Original Research
2015
Gatekeeper role of brain antigen‐presenting CD11c+ cells in neuroinflammation
Paterka M, Siffrin V, Voss JO, Werr J, Hoppmann N, Gollan R, Belikan P, Bruttger J, Birkenstock J, Jung S, Esplugues E, Yogev N, Flavell RA, Bopp T, Zipp F. Gatekeeper role of brain antigen‐presenting CD11c+ cells in neuroinflammation. The EMBO Journal 2015, 35: 89-101. PMID: 26612827, PMCID: PMC4718005, DOI: 10.15252/embj.201591488.Peer-Reviewed Original ResearchConceptsPathogenic T cellsT cellsFrequent chronic inflammatory diseaseChronic inflammatory diseaseAntigen-presenting cellsInflammatory chemokines CCL5Autoimmune neuroinflammationPerivascular clustersTh17 cellsDendritic cellsMultiple sclerosisInflammatory diseasesChemokine CCL5Disease severityCNSGM-CSFExpression correlatesTwo-photon microscopyNeuroinflammationGatekeeper functionSurvivalCellsGatekeeper rolePotent typeImpaired enrichmentA Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control
Xin G, Schauder DM, Lainez B, Weinstein JS, Dai Z, Chen Y, Esplugues E, Wen R, Wang D, Parish IA, Zajac AJ, Craft J, Cui W. A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control. Cell Reports 2015, 13: 1118-1124. PMID: 26527008, PMCID: PMC4859432, DOI: 10.1016/j.celrep.2015.09.069.Peer-Reviewed Original ResearchConceptsCD8 T cellsChronic viral infectionsBATF expressionT cellsIL-21Chronic infectionEffector functionsViral infectionCD8 T cell effector functionsAnti-viral effector functionsCD8 T cell responsesCD8 T cell immunityT cell effector functionT cell immunityCD4 T cellsT cell responsesCell effector functionsT cell persistenceT cell maintenanceBlimp-1 expressionCD8 responsesCD4 helpCell immunityViral controlTranscription factor expressionTh17 cells transdifferentiate into regulatory T cells during resolution of inflammation
Gagliani N, Vesely M, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015, 523: 221-225. PMID: 25924064, PMCID: PMC4498984, DOI: 10.1038/nature14452.Peer-Reviewed Original ResearchConceptsRegulatory T cellsResolution of inflammationInflammatory diseasesT cellsTh17 cellsImmune responseT helper cell typeTherapeutic opportunitiesAnti-inflammatory fateT helper cellsAnti-inflammatory phenotypeHuman inflammatory diseasesBeneficial host responseAryl hydrocarbon receptorIL-17ARegulatory cellsHelper cellsSignature cytokinesMouse modelTranscriptional profilesHost responseInflammationCytokinesHydrocarbon receptorDisease
2014
Dynamic signaling by T follicular helper cells during germinal center B cell selection
Shulman Z, Gitlin AD, Weinstein JS, Lainez B, Esplugues E, Flavell RA, Craft JE, Nussenzweig MC. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 2014, 345: 1058-1062. PMID: 25170154, PMCID: PMC4519234, DOI: 10.1126/science.1257861.Peer-Reviewed Original ResearchConceptsFollicular helper cellsB cellsGC B cellsHelper cellsGerminal centersAntibody-producing B cellsCytokine interleukin-4B cell selectionGerminal center B cell selectionInterleukin-4Transient elevationMajor histocompatibilitySustained increaseFree calciumClonal expansionCognate peptideIntravital imagingCell migrationCellsIntracellularCell selectionHigh levelsHistocompatibilityOct-1 Regulates IL-17 Expression by Directing Interchromosomal Associations in Conjunction with CTCF in T Cells
Kim LK, Esplugues E, Zorca CE, Parisi F, Kluger Y, Kim TH, Galjart NJ, Flavell RA. Oct-1 Regulates IL-17 Expression by Directing Interchromosomal Associations in Conjunction with CTCF in T Cells. Molecular Cell 2014, 54: 56-66. PMID: 24613343, PMCID: PMC4058095, DOI: 10.1016/j.molcel.2014.02.004.Peer-Reviewed Original ResearchAnimalsBinding SitesCCCTC-Binding FactorCell DifferentiationCell LineageCells, CulturedChromosomes, MammalianDeoxyribonuclease IGene Expression RegulationGenes, ReporterGenetic LociGreen Fluorescent ProteinsInterleukin-17MiceMice, Inbred C57BLMice, KnockoutMice, TransgenicOctamer Transcription Factor-1Promoter Regions, GeneticRepressor ProteinsSequence DeletionTh17 CellsTh2 CellsTime Factors
2012
Bcl6 expression specifies the T follicular helper cell program in vivo
Liu X, Yan X, Zhong B, Nurieva RI, Wang A, Wang X, Martin-Orozco N, Wang Y, Chang SH, Esplugues E, Flavell RA, Tian Q, Dong C. Bcl6 expression specifies the T follicular helper cell program in vivo. Journal Of Experimental Medicine 2012, 209: 1841-1852. PMID: 22987803, PMCID: PMC3457730, DOI: 10.1084/jem.20120219.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody FormationCell DifferentiationCluster AnalysisDNA-Binding ProteinsGene ExpressionGene Expression ProfilingGene OrderGene TargetingGenes, ReporterGerminal CenterImmunologic MemoryMiceMice, TransgenicProto-Oncogene Proteins c-bcl-6Receptors, CXCR5T-Lymphocyte SubsetsT-Lymphocytes, Helper-InducerTranscription, GeneticConceptsEffector T cell lineagesFollicular helper cellsT cell differentiationT-cell lineageGerminal center reactionTfh cellsHelper cellsImmune responseReporter miceCenter reactionBCL6 expressionFide markerBona fide markersEarly phaseVivoBCL6Pivotal roleCell lineagesCell differentiationCellsCell programCXCR5TfhTranscription factorsReporter systemEnhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes
Czyzyk J, Henegariu O, Preston-Hurlburt P, Baldzizhar R, Fedorchuk C, Esplugues E, Bottomly K, Gorus FK, Herold K, Flavell RA. Enhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes. The Journal Of Immunology 2012, 188: 6319-6327. PMID: 22593614, PMCID: PMC3370061, DOI: 10.4049/jimmunol.1200467.Peer-Reviewed Original ResearchConceptsAutoimmune diabetes-prone NOD miceDiabetes-prone NOD miceHuman type 1 diabetesAnti-insulin autoantibodiesOnset of diabetesProtective humoral immunityType 1 diabetesNOD miceAutoimmune inflammationIslet inflammationNOD modelSuboptimal doseAutoimmune diseasesHumoral immunityImmunological toleranceT cellsHumoral activityType 1Early onsetDiabetesElevated levelsClade B serpinsAutoantibodiesInflammationProtease inhibitorsMir-33 regulates cell proliferation and cell cycle progression
Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramírez CM, Chamorro-Jorganes A, Wanschel AC, Lasuncion MA, Morales-Ruiz M, Suarez Y, Baldan A, Esplugues E, Fernández-Hernando C. Mir-33 regulates cell proliferation and cell cycle progression. Cell Cycle 2012, 11: 922-933. PMID: 22333591, PMCID: PMC3323796, DOI: 10.4161/cc.11.5.19421.Peer-Reviewed Original ResearchConceptsCell cycle progressionCyclin-dependent kinase 6Cycle progressionCell proliferationCell cycle regulationMiR-33Expression of genesCyclin D1Cell cycle arrestSREBP genesCycle regulationFatty acid metabolismHost genesPosttranscriptional levelGene expressionIntronic sequencesKinase 6Cellular growthCritical regulatorCycle arrestCellular levelLiver regenerationGenesMiR-33 expressionAcid metabolism
2011
Development of Autoimmune Diabetes in the Absence of Detectable IL-17A in a CD8-Driven Virally Induced Model
Van Belle TL, Esplugues E, Liao J, Juntti T, Flavell RA, von Herrath MG. Development of Autoimmune Diabetes in the Absence of Detectable IL-17A in a CD8-Driven Virally Induced Model. The Journal Of Immunology 2011, 187: 2915-2922. PMID: 21832162, PMCID: PMC3169711, DOI: 10.4049/jimmunol.1000180.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell SeparationDiabetes Mellitus, Type 1Disease Models, AnimalFemaleFlow CytometryGene Knock-In TechniquesGenes, ReporterGreen Fluorescent ProteinsInterleukin-17Lymphocytic choriomeningitis virusMaleMiceMice, Inbred C57BLVirus DiseasesConceptsType 1 diabetesIL-17AIL-17IL-17A.T cellsViral infectionAutoimmune diabetes developmentVirus-induced modelIL-17 levelsIL-17A productionΓδ T cellsLymphocytic choriomeningitis virusAutoimmune diabetesAutoimmune disordersChronic inflammationDiabetes developmentViral eliminationReporter miceDiabetesBacterial infectionsInfectionCD8Recent studiesCellsInflammationControl of TH17 cells occurs in the small intestine
Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, O’Connor W, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA. Control of TH17 cells occurs in the small intestine. Nature 2011, 475: 514-518. PMID: 21765430, PMCID: PMC3148838, DOI: 10.1038/nature10228.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesCD3 ComplexCD4-Positive T-LymphocytesCell MovementChemokine CCL20Disease Models, AnimalEncephalomyelitis, Autoimmune, ExperimentalFemaleGene Expression ProfilingGene Expression RegulationInfluenza A virusInterleukin-17Intestine, SmallMaleMiceMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicOrthomyxoviridae InfectionsReceptors, CCR6SepsisStaphylococcal InfectionsTh17 CellsConceptsTh17 cellsImmune systemSmall intestineCD3-specific antibodiesT helper cellsModel of sepsisNumerous autoimmune diseasesRheumatoid arthritisMultiple sclerosisAutoimmune diseasesHelper cellsGastrointestinal tractViral infectionIntestineCellsSepsisTh17ArthritisSclerosisPathogenesisInfectionInfluenzaDiseaseMiceTractmiR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling
Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, Esplugues E, Fisher EA, Penalva LO, Moore KJ, Suárez Y, Lai EC, Fernández-Hernando C. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 9232-9237. PMID: 21576456, PMCID: PMC3107310, DOI: 10.1073/pnas.1102281108.Peer-Reviewed Original ResearchConceptsFatty acid metabolismFatty acid oxidationMiR-33aInsulin receptor substrate 2Sirtuin 6Acid metabolismInsulin-signaling pathwayIntronic microRNAsSterol regulatory element-binding protein 2Acid oxidationHost genesKey enzymeHepatic cell linesMetabolic syndromeCarnitine palmitoyltransferase 1AMetabolic pathwaysSubstrate 2Cellular imbalanceProtein 2Cholesterol homeostasisGenesCell linesLevels of HDLPathwayMetabolism results