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 infection
2023
IL-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 predictionsIL-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 miceA 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 RNA
2022
Human neutrophil development and functionality are enabled in a humanized mouse model
Zheng Y, Sefik E, Astle J, Karatepe K, Öz HH, Solis AG, Jackson R, Luo HR, Bruscia EM, Halene S, Shan L, Flavell RA. Human neutrophil development and functionality are enabled in a humanized mouse model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2121077119. PMID: 36269862, PMCID: PMC9618085, DOI: 10.1073/pnas.2121077119.Peer-Reviewed Original ResearchConceptsHumanized mouse modelMouse modelHuman immune systemHuman neutrophilsImmune systemFunctional human immune systemGranulocyte colony-stimulating factorUnique mouse modelColony-stimulating factorHuman G-CSFMISTRG miceG-CSF receptor geneBacterial burdenInfectious challengeG-CSFNeutrophilsMiceNeutrophil developmentReceptor geneDiseaseRNA m6A demethylase ALKBH5 regulates the development of γδ T cells
Ding C, Xu H, Yu Z, Roulis M, Qu R, Zhou J, Oh J, Crawford J, Gao Y, Jackson R, Sefik E, Li S, Wei Z, Skadow M, Yin Z, Ouyang X, Wang L, Zou Q, Su B, Hu W, Flavell RA, Li HB. RNA m6A demethylase ALKBH5 regulates the development of γδ T cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2203318119. PMID: 35939687, PMCID: PMC9388086, DOI: 10.1073/pnas.2203318119.Peer-Reviewed Original ResearchConceptsDemethylase ALKBH5Messenger RNAΓδ T cellsΓδ T cell biologyCommon posttranscriptional modificationΓδ T cell developmentT cell biologyT cell developmentCell precursorsT cell precursorsMammalian cellsRNA modificationsPosttranscriptional modificationsTissue homeostasisCell biologyT cellsTarget genesCheckpoint roleCell developmentM6A demethylase ALKBH5ALKBH5Γδ T-cell originΓδ T cell repertoireCell populationsEarly developmentInflammasome activation in infected macrophages drives COVID-19 pathology
Sefik E, Qu R, Junqueira C, Kaffe E, Mirza H, Zhao J, Brewer JR, Han A, Steach HR, Israelow B, Blackburn HN, Velazquez SE, Chen YG, Halene S, Iwasaki A, Meffre E, Nussenzweig M, Lieberman J, Wilen CB, Kluger Y, Flavell RA. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature 2022, 606: 585-593. PMID: 35483404, PMCID: PMC9288243, DOI: 10.1038/s41586-022-04802-1.Peer-Reviewed Original ResearchConceptsInflammasome activationLung inflammationInflammatory responseInfected macrophagesSARS-CoV-2 infectionHuman macrophagesChronic lung pathologyPersistent lung inflammationSevere COVID-19Immune inflammatory responseInflammatory cytokine productionHumanized mouse modelNLRP3 inflammasome pathwayCOVID-19 pathologyCOVID-19SARS-CoV-2Productive viral cycleHyperinflammatory stateChronic stageIL-18Cytokine productionInflammatory cytokinesLung pathologyInflammasome pathwayInterleukin-1
2021
A humanized mouse model of chronic COVID-19
Sefik E, Israelow B, Mirza H, Zhao J, Qu R, Kaffe E, Song E, Halene S, Meffre E, Kluger Y, Nussenzweig M, Wilen CB, Iwasaki A, Flavell RA. A humanized mouse model of chronic COVID-19. Nature Biotechnology 2021, 40: 906-920. PMID: 34921308, PMCID: PMC9203605, DOI: 10.1038/s41587-021-01155-4.Peer-Reviewed Original ResearchConceptsChronic COVID-19Humanized mouse modelImmune responseMouse modelAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionCOVID-19Adaptive human immune responsesInterferon-stimulated gene signaturePersistent viral RNACoronavirus 2 infectionPatient-derived antibodiesT-cell lymphopeniaHuman immune responseHyperactive immune responseCoronavirus disease 2019Inflammatory macrophage responseImmunological injuryLung pathologyCell lymphopeniaDisease 2019Severe diseaseRodent modelsInflammatory macrophagesEditorial: Regulatory T Cell Heterogeneity: Canonical and Non-Canonical Functions
Sefik E, Hori S, Vasanthakumar A. Editorial: Regulatory T Cell Heterogeneity: Canonical and Non-Canonical Functions. Frontiers In Immunology 2021, 12: 722563. PMID: 34630397, PMCID: PMC8492903, DOI: 10.3389/fimmu.2021.722563.Peer-Reviewed Original Research
2020
Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses
Low JS, Farsakoglu Y, Vesely M, Sefik E, Kelly JB, Harman CCD, Jackson R, Shyer JA, Jiang X, Cauley LS, Flavell RA, Kaech SM. Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses. Journal Of Experimental Medicine 2020, 217: e20192291. PMID: 32525985, PMCID: PMC7398161, DOI: 10.1084/jem.20192291.Peer-Reviewed Original ResearchConceptsMemory T cellsT cellsLung CD8TRM cellsTissue-resident memory T cellsLong-term protective immunityT cell reactivationCell reactivationPortal of infectionCell functional responsesMemory CD8Protective immunityEffector responsesLymphoid organsCD8Distinct functional responsesFunctional responseReactivationCellsAPCActivation kineticsCritical roleResponseInfectionImmunityAn Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint
Ramanan D, Sefik E, Galván-Peña S, Wu M, Yang L, Yang Z, Kostic A, Golovkina T, Kasper D, Mathis D, Benoist C. An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint. Cell 2020, 181: 1276-1290.e13. PMID: 32402238, PMCID: PMC7393667, DOI: 10.1016/j.cell.2020.04.030.Peer-Reviewed Original ResearchConceptsDouble-negative feedback loopTreg proportionImmunological modeGut immune responseGut commensalsControlling gut inflammationSpecies levelInbred mouse strainsMulti-generational transmissionTreg-dependent mannerCellular perturbationsRegulatory T cellsDisease susceptibilityNon-epigeneticMaternal transmissionInflammatory disease susceptibilityNon-geneticGut inflammationT cellsGenetic tuningMouse strainsImmune responseMultiple generationsImmune systemFeedback loopmRNA destabilization by BTG1 and BTG2 maintains T cell quiescence
Hwang SS, Lim J, Yu Z, Kong P, Sefik E, Xu H, Harman CCD, Kim LK, Lee GR, Li HB, Flavell RA. mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence. Science 2020, 367: 1255-1260. PMID: 32165587, DOI: 10.1126/science.aax0194.Peer-Reviewed Original ResearchEnteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity
Jarret A, Jackson R, Duizer C, Healy ME, Zhao J, Rone JM, Bielecki P, Sefik E, Roulis M, Rice T, Sivanathan KN, Zhou T, Solis AG, Honcharova-Biletska H, Vélez K, Hartner S, Low JS, Qu R, de Zoete MR, Palm NW, Ring AM, Weber A, Moor AE, Kluger Y, Nowarski R, Flavell RA. Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity. Cell 2020, 180: 50-63.e12. PMID: 31923399, PMCID: PMC7339937, DOI: 10.1016/j.cell.2019.12.016.Peer-Reviewed Original ResearchConceptsEnteric nervous systemSingle-cell sequencingMucosal barrier immunitySingle-molecule fluorescenceIL-18Non-redundant roleSitu mRNA hybridization studiesEpithelial cellsUnbiased RNA sequencingRNA sequencingProtein responseBarrier immunityNervous systemConfocal microscopyCytokine IL-18Hybridization studiesInvasive bacterial infectionsSalmonella typhimurium infectionSequencingProfound consequencesIntestinal neuronsEnteric neuronsIntestinal immunityMucosal barrierTyphimurium infection
2018
m6A mRNA methylation sustains Treg suppressive functions
Tong J, Cao G, Zhang T, Sefik E, Amezcua Vesely MC, Broughton JP, Zhu S, Li H, Li B, Chen L, Chang HY, Su B, Flavell RA, Li HB. m6A mRNA methylation sustains Treg suppressive functions. Cell Research 2018, 28: 253-256. PMID: 29303144, PMCID: PMC5799823, DOI: 10.1038/cr.2018.7.Peer-Reviewed Original Research
2017
Mining the Human Gut Microbiota for Immunomodulatory Organisms
Geva-Zatorsky N, Sefik E, Kua L, Pasman L, Tan T, Ortiz-Lopez A, Yanortsang T, Yang L, Jupp R, Mathis D, Benoist C, Kasper D. Mining the Human Gut Microbiota for Immunomodulatory Organisms. Cell 2017, 168: 928-943.e11. PMID: 28215708, PMCID: PMC7774263, DOI: 10.1016/j.cell.2017.01.022.Peer-Reviewed Original ResearchConceptsGut microbiotaHuman gut microbesHuman gut microbiotaIndividual bacterial speciesGut microbesMicrobial phylogenyHuman gutDiverse microbesEpigenetic systemsMicrobial diversityBacterial speciesMicrobiota's abilityMicrobesMicrobiotaMonocolonized miceGutImmunological adaptationsHostImmune systemPhylogenyImmune parametersPhylogeneticallyImmunomodulatory effectsSpeciesDiversity
2016
Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice
Tan T, Sefik E, Geva-Zatorsky N, Kua L, Naskar D, Teng F, Pasman L, Ortiz-Lopez A, Jupp R, Wu H, Kasper D, Benoist C, Mathis D. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e8141-e8150. PMID: 27911839, PMCID: PMC5167147, DOI: 10.1073/pnas.1617460113.Peer-Reviewed Original ResearchConceptsIntestinal Th17 cellsB. adolescentisTh17 cell accumulationTh17 cellsHuman gutBifidobacterium strainsBifidobacterium adolescentisBacterial speciesTranscriptional programsIdentified speciesSymbiont bacteriaCell accumulationProbiotic preparationGut epitheliumInduce Th17 cellsMurine intestineK/BxN mouse modelFunctional microbesInoculation of miceFilamentous bacteriaMicrobesAttending inflammationBacteriaGutAutoimmune arthritis
2015
Control of peripheral tolerance by regulatory T cell–intrinsic Notch signaling
Charbonnier L, Wang S, Georgiev P, Sefik E, Chatila T. Control of peripheral tolerance by regulatory T cell–intrinsic Notch signaling. Nature Immunology 2015, 16: 1162-1173. PMID: 26437242, PMCID: PMC4618075, DOI: 10.1038/ni.3288.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsEpigenesis, GeneticFemaleForkhead Transcription FactorsGraft vs Host DiseaseMaleMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, TransgenicMutationPeripheral ToleranceRapamycin-Insensitive Companion of mTOR ProteinReceptor, Notch1Recombinant Fusion ProteinsSignal TransductionTh1 CellsT-Lymphocytes, RegulatoryTranscriptomeIndividual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells
Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015, 349: 993-997. PMID: 26272906, PMCID: PMC4700932, DOI: 10.1126/science.aaa9420.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBacteriaBacteroidetesColitis, UlcerativeColonForkhead Transcription FactorsHomeostasisHumansImmunity, MucosalIntestinal MucosaMice, Inbred C57BLMicrobiotaNuclear Receptor Subfamily 1, Group F, Member 3SymbiosisTh17 CellsT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryTranscription, GeneticTranscriptomeConceptsRegulatory T cellsImmuno-inflammatory responseT helper 17 (Th17) cell differentiationTranscription factor Foxp3Important effector moleculeRegulatory cellsHuman gut microbiotaFactor Foxp3T cellsRelated cell typesGut microbiotaMouse colonRORγSymbiotic membersIntestinal symbiontsFoxp3Tissue homeostasisEffector moleculesCell differentiationCell typesDistinct populationsCellsDifferent outcomesInflammation