2023
Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice
Nickerson K, Smita S, Hoehn K, Marinov A, Thomas K, Kos J, Yang Y, Bastacky S, Watson C, Kleinstein S, Shlomchik M. Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice. Journal Of Experimental Medicine 2023, 220: e20221346. PMID: 36828389, PMCID: PMC9997508, DOI: 10.1084/jem.20221346.Peer-Reviewed Original Research
2021
Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA
Oh JE, Song E, Moriyama M, Wong P, Zhang S, Jiang R, Strohmeier S, Kleinstein SH, Krammer F, Iwasaki A. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Science Immunology 2021, 6: eabj5129. PMID: 34890255, PMCID: PMC8762609, DOI: 10.1126/sciimmunol.abj5129.Peer-Reviewed Original ResearchConceptsVirus infectionIgA secretionB cellsMucosal surfacesIgA-secreting B cellsIgA-expressing cellsRole of IgARespiratory virus infectionsIgA-secreting cellsLower respiratory tractInfluenza virus infectionEffective immune protectionHeterologous virus infectionMemory B cellsSecretory immunoglobulin AProtein-based vaccinesB cell populationsPredominant Ig isotypeSite of entryIntranasal primingBronchoalveolar spaceProtective immunityVaccine strategiesRespiratory mucosaImmune protectionHeterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders
Brioschi S, Wang WL, Peng V, Wang M, Shchukina I, Greenberg ZJ, Bando JK, Jaeger N, Czepielewski RS, Swain A, Mogilenko DA, Beatty WL, Bayguinov P, Fitzpatrick JAJ, Schuettpelz LG, Fronick CC, Smirnov I, Kipnis J, Shapiro VS, Wu GF, Gilfillan S, Cella M, Artyomov MN, Kleinstein SH, Colonna M. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science 2021, 373 PMID: 34083450, PMCID: PMC8448524, DOI: 10.1126/science.abf9277.Peer-Reviewed Original ResearchConceptsCentral nervous systemMeningeal B cellsB cellsAdaptive immune cellsAntigen-experienced B cellsBone marrow chimerasCNS bordersCNS antigensBlood borneImmune privilegeImmune cellsBone marrow nicheParabiosis experimentsSystemic circulationNervous systemB cell developmentLymphopoietic nicheMeningesMarrow nicheVascular connectionsCell developmentCellsConfocal imagingCalvariaImmunosurveillance
2020
Human germinal centres engage memory and naive B cells after influenza vaccination
Turner JS, Zhou JQ, Han J, Schmitz AJ, Rizk AA, Alsoussi WB, Lei T, Amor M, McIntire KM, Meade P, Strohmeier S, Brent RI, Richey ST, Haile A, Yang YR, Klebert MK, Suessen T, Teefey S, Presti RM, Krammer F, Kleinstein SH, Ward AB, Ellebedy AH. Human germinal centres engage memory and naive B cells after influenza vaccination. Nature 2020, 586: 127-132. PMID: 32866963, PMCID: PMC7566073, DOI: 10.1038/s41586-020-2711-0.Peer-Reviewed Original ResearchConceptsB cell clonesInfluenza vaccinationGerminal center B cellsB cellsGerminal center reactionCell clonesLymph nodesMonoclonal antibodiesPre-existing memory B cellsGerminal center B cell responsesStrain-specific monoclonal antibodiesCenter reactionUltrasound-guided fine-needle aspirationMajor public health threatEarly plasmablast responsesInfluenza virus vaccinationSeasonal influenza vaccinationCross-reactive monoclonal antibodiesB cell responsesMemory B cellsB-cell originFine-needle aspirationNaive B cellsPublic health threatHuman germinal centreA Potently Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection
Alsoussi WB, Turner JS, Case JB, Zhao H, Schmitz AJ, Zhou JQ, Chen RE, Lei T, Rizk AA, McIntire KM, Winkler ES, Fox JM, Kafai NM, Thackray LB, Hassan AO, Amanat F, Krammer F, Watson CT, Kleinstein SH, Fremont DH, Diamond MS, Ellebedy AH. A Potently Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection. The Journal Of Immunology 2020, 205: ji2000583. PMID: 32591393, PMCID: PMC7566074, DOI: 10.4049/jimmunol.2000583.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsAntibodies, MonoclonalAntibodies, NeutralizingAntibodies, ViralBetacoronavirusChlorocebus aethiopsCoronavirus InfectionsCOVID-19Disease Models, AnimalEpitope MappingFemaleHEK293 CellsHumansImmunodominant EpitopesMiceMice, Inbred C57BLPandemicsPeptidyl-Dipeptidase APneumonia, ViralProtein Interaction Domains and MotifsSARS-CoV-2Spike Glycoprotein, CoronavirusTransfectionVero CellsConceptsSARS-CoV-2 infectionSARS-CoV-2Receptor-binding domainSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Angiotensin-converting enzyme 2Human angiotensin-converting enzyme 2Wild-type SARS-CoV-2Lung viral loadsSyndrome coronavirus 2Millions of infectionsTrimeric spike glycoproteinLicensed therapeuticsViral loadCoronavirus 2Systemic disseminationEffective antiviralsEnzyme 2Murine modelMurine mAbsEffective interventionsInfectionWeight lossSpike glycoproteinMutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response
Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, Venturutti L, Rivas MA, Calvo-Fernández MT, Gutierrez J, Camarillo JM, Takata K, Tarte K, Kelleher NL, Steidl C, Mason CE, Elemento O, Allis CD, Kleinstein SH, Melnick AM. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer Cell 2020, 37: 655-673.e11. PMID: 32396861, PMCID: PMC7298875, DOI: 10.1016/j.ccell.2020.04.004.Peer-Reviewed Original ResearchConceptsFollicular lymphomaB cellsIndolent tumorsCell helpFollicular dendritic cell networksB cell requirementDendritic cell networksFollicular helper cellsGerminal center B cellsGC B cellsHelper cellsImmunological nicheImmune responseMalignant transformationHuman follicular lymphomaEZH2 mutationsPrevents inductionFunction mutationsTumorsCell requirementsCellsMutant EZH2LymphomaMutations
2019
Migrant memory B cells secrete luminal antibody in the vagina
Oh JE, Iijima N, Song E, Lu P, Klein J, Jiang R, Kleinstein SH, Iwasaki A. Migrant memory B cells secrete luminal antibody in the vagina. Nature 2019, 571: 122-126. PMID: 31189952, PMCID: PMC6609483, DOI: 10.1038/s41586-019-1285-1.Peer-Reviewed Original ResearchConceptsMemory B cellsFemale reproductive tractB cellsPlasma cellsReproductive tractCD4 tissue-resident memory T cellsTissue-resident memory T cellsLower female reproductive tractHerpes simplex virus 2Genital herpes infectionMemory T cellsExpression of chemokinesSimplex virus 2CXCR3-dependent mannerLocal plasma cellsLuminal antibodyMucosal antibodiesHerpes infectionPrimary infectionMucosal barrierSecondary challengeVariety of pathogensT cellsLamina propriaInducible source
2018
Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers
Rydyznski CE, Cranert SA, Zhou JQ, Xu H, Kleinstein SH, Singh H, Waggoner SN. Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers. Cell Reports 2018, 24: 3367-3373.e4. PMID: 30257198, PMCID: PMC6192537, DOI: 10.1016/j.celrep.2018.08.075.Peer-Reviewed Original ResearchConceptsNK cellsGC B cell frequencyNatural killer cell suppressionAntigen-reactive B cellsB cell frequenciesNatural killer cellsFollicular helper TAntigen-specific immunoglobulinsAdministration of alumGerminal center reactionVaccine elicitationHelper TKiller cellsHumoral immunityProtective antibodiesHigh-affinity antibodiesCell suppressionGerminal centersB cellsCell frequencyCenter reactionSomatic hypermutationGC developmentGC reactionAntibody affinity
2017
Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response
Laidlaw BJ, Lu Y, Amezquita RA, Weinstein JS, Vander Heiden JA, Gupta NT, Kleinstein SH, Kaech SM, Craft J. Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Science Immunology 2017, 2 PMID: 29054998, PMCID: PMC5846620, DOI: 10.1126/sciimmunol.aan4767.Peer-Reviewed Original ResearchConceptsFollicular regulatory T cellsRegulatory T cellsIL-10Lymphocytic choriomeningitis virusT cellsB cellsInterleukin-10GC responseCell-derived IL-10Follicular helper T cellsHelper T cellsB cell responsesGerminal center responseGerminal center developmentActivated B cellsBox protein 1GC B cellsAcute infectionCenter responseCell responsesImportant mediatorNuclear translocationGC reactionProtein 1Forkhead box protein 1
2016
A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data
Cui A, Di Niro R, Vander Heiden JA, Briggs AW, Adams K, Gilbert T, O'Connor KC, Vigneault F, Shlomchik MJ, Kleinstein SH. A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. The Journal Of Immunology 2016, 197: 3566-3574. PMID: 27707999, PMCID: PMC5161250, DOI: 10.4049/jimmunol.1502263.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCells, CulturedClonal Selection, Antigen-MediatedDNA RepairFemaleGerminal CenterHigh-Throughput Nucleotide SequencingHumansImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionMiceMice, Inbred BALB CMice, TransgenicModels, GeneticMutationMutation RateSomatic Hypermutation, ImmunoglobulinConceptsSpecific DNA motifsSimilar biological processesObserved mutation patternDNA repair activityIg sequencesNonfunctional sequencesDNA motifsMutation patternsHigh mutation frequencySelection pressureUnselected mutationsSequencing dataBiological processesFunctional sequencesRepair activityTransition mutationsSomatic hypermutation patternsGerminal center B cellsSomatic hypermutationNext-generation methodsHypermutation patternsMutation frequencyMutationsSequenceMotifRAG1 targeting in the genome is dominated by chromatin interactions mediated by the non-core regions of RAG1 and RAG2
Maman Y, Teng G, Seth R, Kleinstein SH, Schatz DG. RAG1 targeting in the genome is dominated by chromatin interactions mediated by the non-core regions of RAG1 and RAG2. Nucleic Acids Research 2016, 44: 9624-9637. PMID: 27436288, PMCID: PMC5175335, DOI: 10.1093/nar/gkw633.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesChromatinChromatin ImmunoprecipitationGenomeGenomic InstabilityHigh-Throughput Nucleotide SequencingHistonesHomeodomain ProteinsHumansMiceNucleotide MotifsPromoter Regions, GeneticProtein BindingProtein Interaction Domains and MotifsRecombination, GeneticV(D)J RecombinationConceptsAntigen receptor lociNon-core regionsReceptor locusPlant homeodomain (PHD) fingerChIP-seq dataWide bindingChromatin interactionsAdditional chromatinLysine 4Off-target activityGenomic featuresHistone 3Novel roleRAG1LociChromatinGenomeRAG2Observed patternsDistinct modesBindingH3K4me3H3K27acEndonucleaseRelative contributionAge‐associated vascular inflammation promotes monocytosis during atherogenesis
Du W, Wong C, Song Y, Shen H, Mori D, Rotllan N, Price N, Dobrian AD, Meng H, Kleinstein SH, Fernandez‐Hernando C, Goldstein DR. Age‐associated vascular inflammation promotes monocytosis during atherogenesis. Aging Cell 2016, 15: 766-777. PMID: 27135421, PMCID: PMC4933655, DOI: 10.1111/acel.12488.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsAortaAtherosclerosisBlood VesselsCell CountChemotaxisCulture Media, ConditionedDiet, High-FatDown-RegulationHematopoiesisHemodynamicsInflammationInflammation MediatorsInsulin ResistanceInterleukin-6LeukocytosisMacrophagesMaleMiceMice, Inbred C57BLMonocytesOligonucleotide Array Sequence AnalysisReceptors, LDLStromal CellsUp-RegulationConceptsHigh-fat dietVascular inflammationMacrophage accumulationAtherosclerotic aortaBone marrow transplant experimentsStromal factorsElevated blood pressureVascular smooth muscle cellsLow-fat dietSmooth muscle cellsBlood pressurePeripheral monocytosisProinflammatory stateInflammatory stateLDL levelsIL-6Insulin resistancePeripheral bloodEnhanced atherogenesisInflammatory responseMetabolic dysfunctionYoung aortasMurine modelProduction of osteopontinCCL-2
2015
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 2015, 162: 1217-1228. PMID: 26321681, PMCID: PMC4567953, DOI: 10.1016/j.cell.2015.08.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCD4-Positive T-LymphocytesEndoplasmic ReticulumGlycolysisHexokinaseImmunotherapyLymphocytes, Tumor-InfiltratingMelanomaMiceMonitoring, ImmunologicNFATC Transcription FactorsPhosphoenolpyruvateReceptors, Antigen, T-CellSarcoplasmic Reticulum Calcium-Transporting ATPasesSignal TransductionTransforming Growth Factor betaTumor MicroenvironmentConceptsAnti-tumor T cell responsesT cell responsesT cellsEffector functionsCell responsesTumor-reactive T cellsTumor-infiltrating T cellsPhosphoenolpyruvate carboxykinase 1Tumoricidal effector functionsTumor-specific CD4CD8 T cellsT cell activityMelanoma-bearing miceAerobic glycolysisActivated T cellsMetabolic checkpointTumor growthCell activityTumor microenvironmentNFAT SignalingMetabolic reprogrammingCarboxykinase 1Anabolic metabolismCellsATPase activitySalmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation
Di Niro R, Lee SJ, Vander Heiden J, Elsner RA, Trivedi N, Bannock JM, Gupta NT, Kleinstein SH, Vigneault F, Gilbert TJ, Meffre E, McSorley SJ, Shlomchik MJ. Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation. Immunity 2015, 43: 120-131. PMID: 26187411, PMCID: PMC4523395, DOI: 10.1016/j.immuni.2015.06.013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalB-LymphocytesClonal Selection, Antigen-MediatedGerminal CenterImmunoglobulin GLymphocyte ActivationMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutReceptors, Antigen, B-CellSalmonella InfectionsSalmonella typhimuriumSomatic Hypermutation, ImmunoglobulinSpleenConceptsB cell receptorExtrafollicular sitesGerminal centersAffinity maturationInfection of miceB cell responsesB cell activationDetectable antibodiesSomatic hypermutationExtrafollicular responseAntigen microarraysSalmonella infectionAntigen targetsCell activationSalmonella typhimuriumCell responsesBCR specificityFlow cytometryCell receptorMonoclonal antibodiesUndetectable affinityClonal selectionInfectionAntibodiesLaser microdissectionAnalysis of gene–environment interactions in postnatal development of the mammalian intestine
Rakoff-Nahoum S, Kong Y, Kleinstein SH, Subramanian S, Ahern PP, Gordon JI, Medzhitov R. Analysis of gene–environment interactions in postnatal development of the mammalian intestine. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 1929-1936. PMID: 25691701, PMCID: PMC4343130, DOI: 10.1073/pnas.1424886112.Peer-Reviewed Original ResearchConceptsTLR/IL-1RToll-like receptorsPostnatal developmentIntestinal gene expressionMyeloid differentiation factor 88Domain-containing adapter-inducing interferonDifferentiation factor 88Adapter-inducing interferonMast cell homeostasisIntestinal ontogenyReceptor family membersFactor 88WT miceGene expression programsSmooth muscle developmentGene-environment interactionsIL-1RIntestinal physiologyImmune systemKnockout littermatesPostnatal transitionMicrobial colonizationIntestinal contentsGene expressionPubertal maturation
2014
CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype
Zuccarino-Catania GV, Sadanand S, Weisel FJ, Tomayko MM, Meng H, Kleinstein SH, Good-Jacobson KL, Shlomchik MJ. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nature Immunology 2014, 15: 631-637. PMID: 24880458, PMCID: PMC4105703, DOI: 10.1038/ni.2914.Peer-Reviewed Original ResearchTLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation
Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH, Kaech SM. TLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation. The Journal Of Immunology 2014, 192: 4221-4232. PMID: 24659688, PMCID: PMC4071140, DOI: 10.4049/jimmunol.1302569.Peer-Reviewed Original ResearchConceptsT cell differentiationT cellsEffector cellsTLR ligandsToll/IL-1R domain-containing adapterClonal expansionMore memory T cellsMemory T cellsT cell memoryEffector cell expansionTLR4 ligand LPSMonophosphoryl lipid ARole of adjuvantsTLR4 ligand lipopolysaccharideCell differentiationGene expression signaturesMemory CD8LPS-TLR4TLR4 ligandMonophosphoryl lipidLigand LPSLigand lipopolysaccharideAb productionSecondary infectionCell memoryIntegrating B Cell Lineage Information into Statistical Tests for Detecting Selection in Ig Sequences
Uduman M, Shlomchik MJ, Vigneault F, Church GM, Kleinstein SH. Integrating B Cell Lineage Information into Statistical Tests for Detecting Selection in Ig Sequences. The Journal Of Immunology 2014, 192: 867-874. PMID: 24376267, PMCID: PMC4363135, DOI: 10.4049/jimmunol.1301551.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody AffinityAntibody DiversityB-Lymphocyte SubsetsCell LineageClonal Selection, Antigen-MediatedComputer SimulationConfounding Factors, EpidemiologicGene Rearrangement, B-LymphocyteGenes, ImmunoglobulinHumansMiceModels, ImmunologicalModels, StatisticalROC CurveSequence Analysis, DNASomatic Hypermutation, ImmunoglobulinVDJ ExonsConceptsLineage treesHigh-throughput sequencing technologyLineage tree shapesCell lineage informationIg sequencesRatio of replacementTree-shape analysisStatistical frameworkSequence-based methodsBinomial statistical analysisExperimental data setsIndicators of selectionSequencing technologiesLineage informationSequencing depthNumber of generationsData setsHybrid methodVivo selectionSilent mutationsTree shapeStatistical testsSequenceShape analysisMutations
2013
Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells
Katz SG, LaBelle JL, Meng H, Valeriano RP, Fisher JK, Sun H, Rodig SJ, Kleinstein SH, Walensky LD. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells. Blood 2013, 123: 884-893. PMID: 24352880, PMCID: PMC3916879, DOI: 10.1182/blood-2013-04-499079.Peer-Reviewed Original ResearchConceptsMantle cell lymphomaCyclin D1 transgenic miceCyclin D1 overexpressionB cellsCell lymphomaAggressive B-cell lymphomasSubset of miceTransgenic mouse modelB-cell lymphomaDeletion of BimPathogenesis of MCLHuman mantle cell lymphomaDevelopment of MCLStimulation regimensConventional chemotherapyMouse modelLymphoid maturationTransgenic miceLymphomaBIM deletionSelective expansionMiceProapoptotic BimPathogenesisGenetic aberrationsOvercoming NS1-Mediated Immune Antagonism Involves Both Interferon-Dependent and Independent Mechanisms
Thakar J, Schmid S, Duke JL, García-Sastre A, Kleinstein SH. Overcoming NS1-Mediated Immune Antagonism Involves Both Interferon-Dependent and Independent Mechanisms. Journal Of Interferon & Cytokine Research 2013, 33: 700-708. PMID: 23772952, PMCID: PMC3814816, DOI: 10.1089/jir.2012.0113.Peer-Reviewed Original ResearchConceptsNonstructural protein 1Immune antagonismWild-type C57BL/6 miceIFN-independent mechanismsInduction of IFNCritical antiviral cytokinesInduction of IFNB1Host interferon responseEffective IFNInterferon-DependentC57BL/6 miceAntiviral cytokinesInfluenza A.IFNImmune systemInterferon responseFlu strainImmune antagonistsProtein 1H postinfectionIndependent mechanismsInfectionMiceAntagonismIFNB1