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
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
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- and Tissue-Based TherapyCell DifferentiationCell MovementCell ProliferationDiabetes 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
A 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 infectionIntestineCellsSepsisTh17ArthritisSclerosisPathogenesisInfectionInfluenzaDiseaseMiceTractTh17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3− and Foxp3+ Regulatory CD4+ T Cells in an Interleukin-10-Dependent Manner
Huber S, Gagliani N, Esplugues E, O'Connor W, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA. Th17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3− and Foxp3+ Regulatory CD4+ T Cells in an Interleukin-10-Dependent Manner. Immunity 2011, 34: 554-565. PMID: 21511184, PMCID: PMC3113617, DOI: 10.1016/j.immuni.2011.01.020.Peer-Reviewed Original ResearchConceptsIL-10 signalingT cellsIL-10-dependent mannerIL-10-producing cellsIL-17A-producing CD4T cell-specific blockadeT helper 17 (Th17) cellsHelper 17 cellsIL-10 treatmentChronic inflammatory diseaseInterleukin-10 receptorRegulatory CD4Intestinal inflammationRegulatory cellsInflammatory diseasesExtracellular microorganismsReceptor αCell frequencySmall intestineHost defenseCD4Selective increaseDirect signalingVivoCells
2010
CD69 limits early inflammatory diseases associated with immune response to Listeria monocytogenes infection
Vega‐Ramos J, Alari‐Pahissa E, del Valle J, Carrasco‐Marín E, Esplugues E, Borràs M, Martínez‐A C, Lauzurica P. CD69 limits early inflammatory diseases associated with immune response to Listeria monocytogenes infection. Immunology And Cell Biology 2010, 88: 707-715. PMID: 20440294, DOI: 10.1038/icb.2010.62.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteApoptosisDendritic CellsDNA-Binding ProteinsImmunity, InnateInflammationInterferon Type IInterferon-gammaLectins, C-TypeListeriosisLiverMacrophages, PeritonealMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutSpleenT-LymphocytesTransforming Growth Factor beta1ConceptsListeria monocytogenes infectionMonocytogenes infectionT cellsLM-specific T cellsEarly inflammatory diseaseInfection-induced immunopathologyPotent inflammatory responseBone marrow-derived macrophagesMarrow-derived macrophagesWild-type controlsDendritic cellsTh1 cytokinesImmune pathologyLM infectionInflammatory diseasesInflammatory responseImmune responseLymphocyte apoptosisHost protectionSpleen damageDay 1CD69Mouse infectionCell activationIFN enhancement
2006
CD69 targeting differentially affects the course of collagen-induced arthritis
Sancho D, Gómez M, del Hoyo G, Lamana A, Esplugues E, Lauzurica P, Martinez-A C, Sánchez-Madrid F. CD69 targeting differentially affects the course of collagen-induced arthritis. Journal Of Leukocyte Biology 2006, 80: 1233-1241. PMID: 16921025, DOI: 10.1189/jlb.1205749.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntibodies, MonoclonalAntigens, CDAntigens, Differentiation, T-LymphocyteArthritis, ExperimentalCell ProliferationCollagen Type IIImmunoglobulin GInflammationInterferon-gammaLectins, C-TypeLymphocyte DepletionMiceMice, Inbred BALB CMice, Inbred DBAMice, KnockoutT-LymphocytesConceptsCollagen-induced arthritisCII-specific T cellsLymphocyte proliferative responsesChronic inflammatory diseaseActivation of leukocytesWild-type animalsInflammation correlatesAdoptive transferDBA/1 miceProinflammatory cytokinesInflammatory diseasesInflammatory fociCD69 expressionCD69 mAbT cellsImmune responseIFN-gammaInflammatory sitesProliferative responseCD69Type II collagenArthritisDecreased productionDiseaseMice
2005
The Adaptor Protein 3BP2 Binds Human CD244 and Links this Receptor to Vav Signaling, ERK Activation, and NK Cell Killing
Saborit-Villarroya I, Del Valle J, Romero X, Esplugues E, Lauzurica P, Engel P, Martín M. The Adaptor Protein 3BP2 Binds Human CD244 and Links this Receptor to Vav Signaling, ERK Activation, and NK Cell Killing. The Journal Of Immunology 2005, 175: 4226-4235. PMID: 16177062, DOI: 10.4049/jimmunol.175.7.4226.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsAntigens, CDCell Line, TumorCoculture TechniquesCytotoxicity, ImmunologicExtracellular Signal-Regulated MAP KinasesHumansInterferon-gammaKiller Cells, NaturalLigandsMembrane GlycoproteinsMicePhosphorylationReceptors, ImmunologicSignal TransductionSignaling Lymphocytic Activation Molecule FamilyYeastsConceptsERK activationSrc homology 2 domainThree-hybrid analysisDisease gene productCell surface proteinsLymphocytic activation molecule-associated proteinSAP recruitmentAdaptor proteinConsensus motifGene productsAdaptor 3BP2CD150 familySurface proteinsSAP associationPhysical interactionProteinCellular activationPhosphorylationCell killingMyeloid cellsMotifCellsActivationBindingPresent evidence