2024
The human CD47 checkpoint is targeted by an immunosuppressive Aedes aegypti salivary factor to enhance arboviral skin infectivity
Marin-Lopez A, Huck J, Esterly A, Azcutia V, Rosen C, Garcia-Milian R, Sefik E, Vidal-Pedrola G, Raduwan H, Chen T, Arora G, Halene S, Shaw A, Palm N, Flavell R, Parkos C, Thangamani S, Ring A, Fikrig E. The human CD47 checkpoint is targeted by an immunosuppressive Aedes aegypti salivary factor to enhance arboviral skin infectivity. Science Immunology 2024, 9: eadk9872. PMID: 39121194, DOI: 10.1126/sciimmunol.adk9872.Peer-Reviewed Original ResearchConceptsSuppress antiviral responsesArthropod proteinsPathogen replicationAntiviral responseProtein AVertebrate hostsMosquito salivary proteinsUp-regulatedBlood feedingHuman macrophagesPleomorphic effectsSkin infectionsZika virus disseminationInhibit proinflammatory responsesSalivary proteinsProteinNatural ligandWhite blood cellsHuman skin explantsProinflammatory responseMosquito salivaVirus disseminationHuman CD47Salivary factorsArbovirus infectionUBXN3B is crucial for B lymphopoiesis
Geng T, Yang D, Lin T, Harrison A, Wang B, Cao Z, Torrance B, Fan Z, Wang K, Wang Y, Yang L, Haynes L, Cheng G, Vella A, Flavell R, Pereira J, Fikrig E, Wang P. UBXN3B is crucial for B lymphopoiesis. EBioMedicine 2024, 106: 105248. PMID: 39018756, PMCID: PMC11287013, DOI: 10.1016/j.ebiom.2024.105248.Peer-Reviewed Original ResearchUbiquitin regulatory XPre-BCR signalingB cell receptorB lymphopoiesisKnockout miceValosin-containing proteinCaspase-3 protein levelsCell cycle arrestBone marrow transferNormal B lymphopoiesisUbiquitin ligaseIncreased viral loadCell-intrinsic mannerPathogenesis of severe acute respiratory syndrome coronavirus 2RNA sequencingCycle arrestDNA virusesCell survivalMarrow transferMultiple virusesSingle-cellImmunofluorescence microscopyViral loadMature BRespiratory virusesA metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance
Mertens R, Misra A, Xiao P, Baek S, Rone J, Mangani D, Sivanathan K, Arojojoye A, Awuah S, Lee I, Shi G, Petrova B, Brook J, Anderson A, Flavell R, Kanarek N, Hemberg M, Nowarski R. A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance. Immunity 2024, 57: 2077-2094.e12. PMID: 38906145, DOI: 10.1016/j.immuni.2024.06.001.Peer-Reviewed Original ResearchFatty acid oxidationStimulator of interferon genesMetabolic switchIL-18Immune toleranceIntestinal toleranceRelease of mitochondrial DNAActivation of stimulator of interferon genesSusceptibility to inflammationIL-18 stimulationIL-18 activityMitochondrial DNATolerogenic macrophagesChronic inflammationInterleukin-18Immune stateInflammatory challengeInflammatory responseMetabolic programmingSodium influxMacrophage-derivedImmune functionInterferon genesBistable switchAcid oxidationDeleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies
Wu M, Valenca-Pereira F, Cendali F, Giddings E, Pham-Danis C, Yarnell M, Novak A, Brunetti T, Thompson S, Henao-Mejia J, Flavell R, D’Alessandro A, Kohler M, Rincon M. Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies. Nature Communications 2024, 15: 4444. PMID: 38789421, PMCID: PMC11126743, DOI: 10.1038/s41467-024-48653-y.Peer-Reviewed Original ResearchConceptsMethylation-controlled J proteinCAR-T cellsEfficacy of adoptive T cell therapyCD8+ CAR T cellsAdoptive T cell therapyT-cell therapyCD8 cellsT cellsOvalbumin (OVA)-specific CD8T cell adoptive therapyCD8+ T cellsMelanoma tumors in vivoFunction of T cellsAdoptive cellular therapyMurine B-cell leukemiaPromote T cell functionB-cell leukemiaT cell functionTumors in vivoPre-clinical studiesAnti-tumor activityIn vivo efficacyAdoptive therapyPotential therapeutic strategyEndogenous negative regulatorGene trajectory inference for single-cell data by optimal transport metrics
Qu R, Cheng X, Sefik E, Stanley III J, Landa B, Strino F, Platt S, Garritano J, Odell I, Coifman R, Flavell R, Myung P, Kluger Y. Gene trajectory inference for single-cell data by optimal transport metrics. Nature Biotechnology 2024, 1-11. PMID: 38580861, PMCID: PMC11452571, DOI: 10.1038/s41587-024-02186-3.Peer-Reviewed Original ResearchGene dynamicsGene programTrajectory inferenceBiological processesCell-cell graphDynamics of genesCell trajectory inferenceSingle-cell RNA sequencingSingle-cell dataCell state transitionsMyeloid lineage maturationDynamics of biological processesGene distributionRNA sequencingPseudotemporal orderingGene processingTrajectories of cellsGenesActivity of biological processesTechnical noiseGroups of cellsLineage maturationCellsConstruct cellsSequenceIL-10 constrains sphingolipid metabolism to limit inflammation
York A, Skadow M, Oh J, Qu R, Zhou Q, Hsieh W, Mowel W, Brewer J, Kaffe E, Williams K, Kluger Y, Smale S, Crawford J, Bensinger S, Flavell R. IL-10 constrains sphingolipid metabolism to limit inflammation. Nature 2024, 627: 628-635. PMID: 38383790, PMCID: PMC10954550, DOI: 10.1038/s41586-024-07098-5.Peer-Reviewed Original ResearchActivity of RelCeramide productionVery long chainFatty acid synthesis pathwayCeramide synthase 2Fatty acid homeostasisMetabolic fluxAvailable to cellsRegulatory nodesTranscription factorsCeramide accumulationSynthesis pathwayVLC ceramidesIL-10 deficiencyGene expressionSphingolipid metabolismAcid homeostasisAberrant activationIL-10Cell types1Innate immune cellsInflammatory gene expressionCeramideSignaling resultsGenetic deletion
2023
Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection
Torcellan T, Friedrich C, Doucet-Ladevèze R, Ossner T, Solé V, Riedmann S, Ugur M, Imdahl F, Rosshart S, Arnold S, de Agüero M, Gagliani N, Flavell R, Backes S, Kastenmüller W, Gasteiger G. Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection. Immunity 2023, 57: 124-140.e7. PMID: 38157853, PMCID: PMC10783803, DOI: 10.1016/j.immuni.2023.11.018.Peer-Reviewed Original ResearchConceptsNK cellsTrNK cellsAcute infectionTissue residencySecondary infectionTissue-resident NK cellsConventional NK cellsDistinct developmental requirementsNK cell responsesNatural killer cellsTranscriptional regulator Blimp1Effector cellsKiller cellsCNK cellsPrevious infectionEffector responsesEffector functionsBacterial infectionsCell responsesInfectionRestricted expressionTerms of ontogenyTissueCell formationHuman tissues1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. 1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma. 2023, a1133-a1133. DOI: 10.1136/jitc-2023-sitc2023.1025.Peer-Reviewed Original ResearchALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control
Gao Y, Zimmer J, Vasic R, Liu C, Gbyli R, Zheng S, Patel A, Liu W, Qi Z, Li Y, Nelakanti R, Song Y, Biancon G, Xiao A, Slavoff S, Kibbey R, Flavell R, Simon M, Tebaldi T, Li H, Halene S. ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control. Cell Reports 2023, 42: 113163. PMID: 37742191, PMCID: PMC10636609, DOI: 10.1016/j.celrep.2023.113163.Peer-Reviewed Original ResearchConceptsAlkB homolog 5Post-transcriptional regulatory mechanismsHematopoietic stemNumerous cellular processesProgenitor cell fitnessEnergy metabolismMitochondrial ATP productionMethyladenosine (m<sup>6</sup>A) RNA modificationTricarboxylic acid cycleCell energy metabolismHuman hematopoietic cellsMitochondrial energy productionCell fitnessCellular processesRNA modificationsRNA methylationRegulatory mechanismsEnzyme transcriptsATP productionHomolog 5Acid cycleΑ-ketoglutarateHematopoietic cellsMessenger RNAΑ-KGIL-6 trans-signaling in a humanized mouse model of scleroderma
Odell I, Agrawal K, Sefik E, Odell A, Caves E, Kirkiles-Smith N, Horsley V, Hinchcliff M, Pober J, Kluger Y, Flavell R. IL-6 trans-signaling in a humanized mouse model of scleroderma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2306965120. PMID: 37669366, PMCID: PMC10500188, DOI: 10.1073/pnas.2306965120.Peer-Reviewed Original ResearchConceptsBone marrow-derived immune cellsIL-6Human hematopoietic stem cellsImmune cellsT cellsScleroderma skinSoluble IL-6 receptorCD8 T cellsHumanized mouse modelPathogenesis of sclerodermaMesenchymal cellsFibroblast-derived IL-6IL-6 receptorIL-6 signalingT cell activationHuman IL-6Human T cellsExpression of collagenFibrosis improvementPansclerotic morpheaHuman endothelial cellsHumanized miceReduced markersSkin graftsHuman CD4Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions
Kaffe E, Roulis M, Zhao J, Qu R, Sefik E, Mirza H, Zhou J, Zheng Y, Charkoftaki G, Vasiliou V, Vatner D, Mehal W, AlcHepNet, Kluger Y, Flavell R. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell 2023, 186: 3793-3809.e26. PMID: 37562401, PMCID: PMC10544749, DOI: 10.1016/j.cell.2023.07.017.Peer-Reviewed Original ResearchConceptsMetabolic functionsSpecies-specific interactionsKey metabolic functionsCell-autonomous mechanismsNon-alcoholic fatty liver diseaseMajor metabolic hubNon-parenchymal cellsMetabolic hubHuman hepatocytesMicroenvironmental regulationHuman diseasesHuman-specific aspectsHuman pathologiesHomeostatic processesSpecies mismatchCholesterol uptakeFatty liver diseaseParacrine mannerHuman immuneBile acid conjugationSinusoidal endothelial cellsHepatic metabolic functionMouse liverEndothelial cellsCellsAutologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Chiorazzi M, Martinek J, Krasnick B, Zheng Y, Robbins K, Qu R, Kaufmann G, Skidmore Z, Juric M, Henze L, Brösecke F, Adonyi A, Zhao J, Shan L, Sefik E, Mudd J, Bi Y, Goedegebuure S, Griffith M, Griffith O, Oyedeji A, Fertuzinhos S, Garcia-Milian R, Boffa D, Detterbeck F, Dhanasopon A, Blasberg J, Judson B, Gettinger S, Politi K, Kluger Y, Palucka K, Fields R, Flavell R. Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment. Journal For ImmunoTherapy Of Cancer 2023, 11: e006921. PMID: 37487666, PMCID: PMC10373695, DOI: 10.1136/jitc-2023-006921.Peer-Reviewed Original ResearchConceptsHuman tumor microenvironmentTumor microenvironmentTumor-immune interactionsSolid tumorsAdaptive immune activationAdaptive immune populationsIndividual tumor microenvironmentsPatient's hematopoietic systemPatient-derived xenograft tissuesVascular endothelial growth factorBone marrow hematopoietic stemBone marrow aspiratePreclinical drug testingEndothelial growth factorHematopoietic systemAutologous tumorPDX modelingPDX miceImmune activationImmune populationsMarrow aspiratesAutologous systemIndividual patientsLittermate controlsPreclinical predictionsNew insights into programmed cell death protein 1 blockade-associated cutaneous immune-related adverse events
Micevic G, Daniels A, Flavell R. New insights into programmed cell death protein 1 blockade-associated cutaneous immune-related adverse events. British Journal Of Dermatology 2023, 189: 355-357. PMID: 37471669, PMCID: PMC10503525, DOI: 10.1093/bjd/ljad236.Peer-Reviewed Original ResearchConceptsCutaneous immune-related adverse eventsImmune-related adverse eventsSelf-reactive T cellsCheckpoint receptor PD-1PD-1 inhibitorsHalf of patientsImmune checkpoint blockadeAntitumor immune responseReceptor PD-1Adverse eventsCheckpoint blockadePD-1Immune toleranceCTLA-4T cellsImmune responseLandmark studiesMolecular mechanismsFunctional roleCritical functional rolePatientsBlockadeDermatologistsImportant cluesIL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2304319120. PMID: 37459511, PMCID: PMC10372654, DOI: 10.1073/pnas.2304319120.Peer-Reviewed Original ResearchConceptsIL-7R expressionT cellsIL-7RAntitumor memorySuperior antitumor efficacyCell-based therapiesTumor-specific T cellsAntigen-specific T cellsAntitumor efficacyPowerful antitumor immune responseMarkers of exhaustionTumor-specific CD8Antitumor immune responseIndependent prognostic factorAntitumor immune memoryMemory T cellsMajor risk factorSuperior antitumor activityFunctional CD8Memory CD8Prognostic factorsSurgical resectionAdvanced melanomaLymph nodesNaive miceMETTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells
Xiao Z, Wang S, Tian Y, Lv W, Sheng H, Zhan M, Huang Q, Zhang Z, Zhu L, Zhu C, Zhong H, Wen Q, Liu Z, Tan J, Xu Y, Yang M, Liu Y, Flavell R, Yang Q, Cao G, Yin Z. METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells. Cell Reports 2023, 42: 112684. PMID: 37355989, DOI: 10.1016/j.celrep.2023.112684.Peer-Reviewed Original ResearchConceptsM6A methylationMRNA stabilityΓδ T17 cellsEndogenous double-stranded RNADouble-stranded RNAActivation of STAT1MRNA metabolismMRNA turnoverGene expressionKey enzymeDsRNA contentT17 cellsMethylationFunctional specializationRNA contentΓδ TCritical roleMETTL3Numerous aspectsCellsT17Distinct subsetsM6ATranscriptsRNAGasdermin D licenses MHCII induction to maintain food tolerance in small intestine
He K, Wan T, Wang D, Hu J, Zhou T, Tao W, Wei Z, Lu Q, Zhou R, Tian Z, Flavell R, Zhu S. Gasdermin D licenses MHCII induction to maintain food tolerance in small intestine. Cell 2023, 186: 3033-3048.e20. PMID: 37327784, DOI: 10.1016/j.cell.2023.05.027.Peer-Reviewed Original ResearchConceptsIntestinal epithelial cellsCleavage fragmentsSmall intestineCaspase-3/7 inhibitorRegulatory hubTolerance phenotypeN-terminal fragmentHost cellsDifferential cleavageCaspase-3/7Upper small intestineTranscription of CIITAGasdermin DEpithelial cellsMHCII deficiencyMHCII inductionDietary antigensTr1 cellsImmune toleranceProtective immunityFood toleranceForeign antigensMHCII moleculesMiceCellsA Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver
Ding C, Yu Z, Sefik E, Zhou J, Kaffe E, Wang G, Li B, Flavell R, Hu W, Ye Y, Li H. A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver. Nature Aging 2023, 3: 813-828. PMID: 37277640, DOI: 10.1038/s43587-023-00428-8.Peer-Reviewed Original ResearchConceptsAged miceLiver diseaseLiver microenvironmentAge-related liver diseasesYin Yang 1Liver immune microenvironmentRegulatory T cellsTreg-specific deletionPotential therapeutic targetMitochondrial functionYang 1Treg apoptosisTreg homeostasisTreg cellsTreg functionImmune microenvironmentLiver fibrosisMetabolic dysfunctionOptimal mitochondrial functionYoung miceT cellsLiver cancerTherapeutic targetAged liverLong noncoding RNACutting Edge: IL-21 and Tissue-Specific Signals Instruct Tbet+CD11c+ B Cell Development following Viral Infection.
Song W, Sanchez G, Mayer D, Blackburn H, Chernova I, Flavell R, Weinstein J, Craft J. Cutting Edge: IL-21 and Tissue-Specific Signals Instruct Tbet+CD11c+ B Cell Development following Viral Infection. The Journal Of Immunology 2023, 210: 1861-1865. PMID: 37133336, PMCID: PMC10247523, DOI: 10.4049/jimmunol.2300027.Peer-Reviewed Original ResearchConceptsAge-associated B cellsIL-21Acute lymphocytic choriomeningitis virus infectionB cellsLymphocytic choriomeningitis virus infectionB cell activationHumoral immunityLymphoid organsVirus infectionMouse modelViral infectionB cell developmentCell activationLymphotoxin αVivo generationTissue-specific signalsInfectionDe novo generationOrgan contributionIFNTissue microenvironmentCell developmentLiverPivotal contributorStage-specific roles
2022
Cholinergic control of Th17 cell pathogenicity in experimental autoimmune encephalomyelitis
Nechanitzky R, Nechanitzky D, Ramachandran P, Duncan G, Zheng C, Göbl C, Gill K, Haight J, Wakeham A, Snow B, Bradaschia-Correa V, Ganguly M, Lu Z, Saunders M, Flavell R, Mak T. Cholinergic control of Th17 cell pathogenicity in experimental autoimmune encephalomyelitis. Cell Death & Differentiation 2022, 30: 407-416. PMID: 36528755, PMCID: PMC9950465, DOI: 10.1038/s41418-022-01092-y.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisTh17 cellsMultiple sclerosisAutoimmune encephalomyelitisChAT expressionBrain-infiltrating immune cellsStrong TCR signalingCholinergic controlTherapeutic immunomodulationCholine acetyltransferaseImmune cellsCell pathogenicityDisease progressionChronic activationMouse modelTranscription factor Bhlhe40Novel targetAcetylcholineMRNA levelsPathogenic determinantsTCR signalingEncephalomyelitisCellsExpressionIL17Epiregulin is a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis
Odell I, Steach H, Gauld S, Reinke-Breen L, Karman J, Carr T, Wetter J, Phillips L, Hinchcliff M, Flavell R. Epiregulin is a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis. Science Immunology 2022, 7: eabq6691. PMID: 36490328, PMCID: PMC9840167, DOI: 10.1126/sciimmunol.abq6691.Peer-Reviewed Original ResearchConceptsLung fibrosisDendritic cellsImmune cellsDiffuse cutaneous systemic sclerosisPersistence of fibrosisCutaneous systemic sclerosisExtent of fibrosisType I interferonSystemic sclerosisAutoimmune diseasesAntifibrotic targetsTherapeutic administrationMouse modelI interferonLung samplesLung explantsFibrosisFibrotic tissueImmune signalsEpiregulin expressionPatient's skinExtracellular matrix productionGenetic deficiencyEpiregulinEGFR ligands