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 infectionDeleting 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 regulator
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 tissuesALKBH5 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 mice
2022
Cellular Stress-Induced Metabolites in Escherichia coli
Gatsios A, Kim C, York A, Flavell R, Crawford J. Cellular Stress-Induced Metabolites in Escherichia coli. Journal Of Natural Products 2022, 85: 2626-2640. PMID: 36346625, PMCID: PMC9949963, DOI: 10.1021/acs.jnatprod.2c00706.Peer-Reviewed Original ResearchHIV-1 Vpu restricts Fc-mediated effector functions in vivo
Prévost J, Anand S, Rajashekar J, Zhu L, Richard J, Goyette G, Medjahed H, Gendron-Lepage G, Chen H, Chen Y, Horwitz J, Grunst M, Zolla-Pazner S, Haynes B, Burton D, Flavell R, Kirchhoff F, Hahn B, Smith A, Pazgier M, Nussenzweig M, Kumar P, Finzi A. HIV-1 Vpu restricts Fc-mediated effector functions in vivo. Cell Reports 2022, 41: 111624. PMID: 36351384, PMCID: PMC9703018, DOI: 10.1016/j.celrep.2022.111624.Peer-Reviewed Original ResearchConceptsAntibody-dependent cellular cytotoxicityEffector functionsFc-mediated effector functionsHIV-1-infected cellsWild-type virusCorrelates of protectionRV144 vaccine trialHIV-1 infectionNon-neutralizing antibodiesFc effector functionsCell surface CD4Viral envelope glycoproteinsViral loadHumanized miceHumoral responseVaccine trialsCellular cytotoxicityHIV-1 VpuVpu expressionEnvelope glycoproteinInfected cellsNnAbsVirusVpuAdministrationHuman 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 geneDiseaseN‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling
Cho W, York AG, Wang R, Wyche TP, Piizzi G, Flavell RA, Crawford JM. N‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling. ChemBioChem 2022, 23: e202200490-e202200490. PMID: 36112057, PMCID: PMC9762135, DOI: 10.1002/cbic.202200490.Peer-Reviewed Original ResearchConceptsN-acyl amidesGram-negative opportunistic pathogenNeisseria meningitidisHuman-associated bacteriaBlood-brain barrierBioactive small moleculesInterleukin-10 signalingMacrophage cell typesN-acyltransferaseInterleukin-17AG proteinsHuman diseasesT cellsReceptor signalingCell typesImmune systemHigh mortalityHuman microbiotaRepresentative membersOpportunistic pathogenMeningitidisSignalingSmall moleculesN.MeningitisLACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages
Wei Z, Oh J, Flavell RA, Crawford JM. LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. Nature 2022, 609: 348-353. PMID: 35978195, PMCID: PMC9813773, DOI: 10.1038/s41586-022-05111-3.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseWild-type activityCentral regulatory roleMammalian immune systemBone marrow-derived macrophagesInflammatory macrophagesBiochemical functionsBowel diseaseSignaling outcomesMarrow-derived macrophagesPattern recognition receptorsInflammatory diseasesBiochemical roleRegulatory roleMechanistic connectionUnidentified pathwaySalmonella enterica TyphimuriumNitric oxide synthaseRecognition receptorsHost damageHuman inflammatory diseasesMultiple inflammatory diseasesEnterica TyphimuriumOrnithine decarboxylaseLACC1IL18 signaling causes islet β cell development and insulin secretion via different receptors on acinar and β cells
Zhang X, Luo S, Wang M, Huang Q, Fang W, Li J, Liu T, Zhang Y, Deng Z, Liu CL, Guan S, Ayala JE, Flavell RA, Kulkarni RN, Libby P, Guo J, Liu Z, Shi GP. IL18 signaling causes islet β cell development and insulin secretion via different receptors on acinar and β cells. Developmental Cell 2022, 57: 1496-1511.e6. PMID: 35675813, PMCID: PMC9233156, DOI: 10.1016/j.devcel.2022.05.013.Peer-Reviewed Original ResearchConceptsGlucagon-like peptide-1Β-cell proliferationInsulin secretionΒ-cellsMacrophage expansionDiet-induced glucose intoleranceCell apoptosisIslet β-cell functionAcinar cellsCell proliferationΒ-cell functionIslet α-cellsCell developmentIL18 receptorΒ-cell apoptosisΒ-cell developmentDiabetic patientsGlucose intoleranceGlucose toleranceMacrophage accumulationInsulin sensitivityGLP1 receptorIslet sizePeptide-1Mouse pancreasesInhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis
Damsky W, Wang A, Kim DJ, Young BD, Singh K, Murphy MJ, Daccache J, Clark A, Ayasun R, Ryu C, McGeary MK, Odell ID, Fazzone-Chettiar R, Pucar D, Homer R, Gulati M, Miller EJ, Bosenberg M, Flavell RA, King B. Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis. Nature Communications 2022, 13: 3140. PMID: 35668129, PMCID: PMC9170782, DOI: 10.1038/s41467-022-30615-x.Peer-Reviewed Original ResearchConceptsType 1 immunityInternal organ involvementOrgan involvementT cell-derived IFNIdiopathic inflammatory disorderOpen-label trialMonths of treatmentType 1 cytokinesJanus kinase inhibitorImmunologic changesLongstanding sarcoidosisSarcoidosis activitySarcoidosis symptomsClinical improvementCutaneous sarcoidosisSecondary outcomesComplete responsePrimary outcomeTofacitinib treatmentActivity scoreCytokine mediatorsIL-12IL-15IL-6Inflammatory disorders
2020
Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6+B helper T cells in systemic lupus erythematosus
Facciotti F, Larghi P, Bosotti R, Vasco C, Gagliani N, Cordiglieri C, Mazzara S, Ranzani V, Rottoli E, Curti S, Penatti A, Karnani B, Kobayashi Y, Crosti M, Bombaci M, van Hamburg JP, Rossetti G, Gualtierotti R, Gerosa M, Gatti S, Torretta S, Pignataro L, Tas SW, Abrignani S, Pagani M, Grassi F, Meroni PL, Flavell RA, Geginat J. Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6+B helper T cells in systemic lupus erythematosus. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 7305-7316. PMID: 32184325, PMCID: PMC7132288, DOI: 10.1073/pnas.1917834117.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusHelper T cellsT cellsIL-10Pathogenic roleSLE patientsLupus erythematosusIL-7RB cellsPathogenic anti-dsDNA antibodiesFollicular helper T cellsAnti-dsDNA antibodiesLupus-like diseaseT cell populationsB cell responsesProduction ex vivoCytokine reporter miceProminent pathogenic roleImmunoglobulin G productionNaïve B cellsIL-17Antiinflammatory cytokinesLymph nodesInterleukin-10Peripheral blood
2018
Family‐based study reveals decreased abundance of sputum Granulicatella in asthmatics
Wang L, de Ángel Solá D, Mao Y, Bielecki P, Zhu Y, Sun Z, Shan L, Flavell R, Bazzy‐Asaad A, DeWan A. Family‐based study reveals decreased abundance of sputum Granulicatella in asthmatics. Allergy 2018, 73: 1918-1921. PMID: 29862523, PMCID: PMC6586473, DOI: 10.1111/all.13493.Peer-Reviewed Original Research
2014
Immunoglobulin A Coating Identifies Colitogenic Bacteria in Inflammatory Bowel Disease
Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J, Hao L, Degnan PH, Hu J, Peter I, Zhang W, Ruggiero E, Cho JH, Goodman AL, Flavell RA. Immunoglobulin A Coating Identifies Colitogenic Bacteria in Inflammatory Bowel Disease. Cell 2014, 158: 1000-1010. PMID: 25171403, PMCID: PMC4174347, DOI: 10.1016/j.cell.2014.08.006.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseBowel diseaseIgA coatingIntestinal microbiotaIntestinal bacteriaGerm-free miceIBD patientsIntestinal diseaseImmunoglobulin AMouse modelDiseaseAnaerobic culturingDramatic susceptibilityTargeted eliminationDisease developmentDisease susceptibilityMiceCell sortingMicrobiotaBacterial cell sortingFecal bacteriaSuch bacteriaColitisPatientsIgAInflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota
Gagliani N, Palm NW, de Zoete MR, Flavell RA. Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota. International Immunology 2014, 26: 495-499. PMID: 24948595, PMCID: PMC4200027, DOI: 10.1093/intimm/dxu066.Peer-Reviewed Original ResearchConceptsIntestinal homeostasisInflammatory responsePathological tissue damageImmediate inflammatory responseConflicting studiesEnteric infectionsIntestinal microbiotaTissue damageInflammasome deficiencyInflammasomeStress-associated signalsInfectionPotential roleMicrobiotaHomeostasisCytosolic protein complexesRecent studies