2024
Memory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states
Callahan D, Smita S, Joachim S, Hoehn K, Kleinstein S, Weisel F, Chikina M, Shlomchik M. Memory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states. Nature Immunology 2024, 25: 562-575. PMID: 38200277, DOI: 10.1038/s41590-023-01721-9.Peer-Reviewed Original ResearchGerminal center B cellsDistinct genomic featuresDP cellsDevelopmental originsEpigenetic stateFunctional diversityEpigenetic patternsTranscriptional profilingGenomic featuresDN cellsDistinct developmental historiesB cellsReporter miceFunctional responseCellsMemory B cellsChromatinB cell subsetsCell-dependent responsesMultiple approachesProgenyDiversityT cell-dependent responsesGerminal centersDevelopmental history
2023
Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine
de Assis F, Hoehn K, Zhang X, Kardava L, Smith C, Merhebi O, Buckner C, Trihemasava K, Wang W, Seamon C, Chen V, Schaughency P, Cheung F, Martins A, Chiang C, Li Y, Tsang J, Chun T, Kleinstein S, Moir S. Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine. Cell Reports 2023, 42: 112780. PMID: 37440409, PMCID: PMC10529190, DOI: 10.1016/j.celrep.2023.112780.Peer-Reviewed Original ResearchConceptsMemory B cellsB cell receptorB cellsAtypical memory B cellsInfection-naïve individualsTwo-dose SARSSARS-CoV-2 mRNAB cell responsesAntibody-secreting cellsMonth 6Protective immunityCell responsesCell receptorClonal expansionImmunoglobulin GEarly timepointsLater timepointsPlasmablastsVaccinationCD71TimepointsSurface proteinsCellsMultimodal single-cell analysisMRNA
2021
Cutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19
Hoehn KB, Ramanathan P, Unterman A, Sumida TS, Asashima H, Hafler DA, Kaminski N, Dela Cruz CS, Sealfon SC, Bukreyev A, Kleinstein SH. Cutting Edge: Distinct B Cell Repertoires Characterize Patients with Mild and Severe COVID-19. The Journal Of Immunology 2021, 206: 2785-2790. PMID: 34049971, PMCID: PMC8627528, DOI: 10.4049/jimmunol.2100135.Peer-Reviewed Original ResearchConceptsSevere COVID-19Mild COVID-19B cell responsesMemory B cellsB cell repertoireB cellsCell repertoireCOVID-19Cell responsesExtrafollicular B cell responsesLong-term immunitySymptomatic COVID-19Onset of symptomsB cell populationsGerminal center reactionProtective immunityPlasma cellsSingle-cell RNA sequencingCenter reactionPatientsCell populationsImmunityRNA sequencingCellsPostvaccinationHeterogeneity 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
Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses
Jiang R, Fichtner ML, Hoehn KB, Pham MC, Stathopoulos P, Nowak RJ, Kleinstein SH, O'Connor KC. Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses. JCI Insight 2020, 5 PMID: 32573488, PMCID: PMC7453893, DOI: 10.1172/jci.insight.136471.Peer-Reviewed Original ResearchConceptsMuscle-specific kinase myasthenia gravisMemory B cellsB cell subsetsAntibody-secreting cellsB cellsCell subsetsAutoantibody-producing B cellsB-cell depleting therapyCell-depleting therapyB cell clonesB cell survivalGene expression signaturesMyasthenia gravisAutoimmune disordersRelapseB cell samplesReceptor profilingCell clonesExpression signaturesRituximabTherapyCell survivalCellsTreatmentCell samplesMutant 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
2018
Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue
Zhao Y, Uduman M, Siu JHY, Tull TJ, Sanderson JD, Wu YB, Zhou JQ, Petrov N, Ellis R, Todd K, Chavele KM, Guesdon W, Vossenkamper A, Jassem W, D’Cruz D, Fear DJ, John S, Scheel-Toellner D, Hopkins C, Moreno E, Woodman NL, Ciccarelli F, Heck S, Kleinstein SH, Bemark M, Spencer J. Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue. Nature Communications 2018, 9: 3857. PMID: 30242242, PMCID: PMC6155012, DOI: 10.1038/s41467-018-06089-1.Peer-Reviewed Original ResearchConceptsMemory B cellsMZ B cellsLymphoid tissueB cellsClassical memory B cellsMemory B cell populationsDistant lymphoid tissuesGut lymphoid tissueExpression of CD27Marginal zone B cellsB cell poolHuman memory B cellsB cell populationsSomatic mutationsMicroanatomical nichesGerminal centersPhenotypic progressionCell poolMass cytometryCell populationsIGHV repertoireTissueMarginal zoneCellsPopulation
2017
Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8+ T Cell Terminal Differentiation and Loss of Multipotency
Gray SM, Amezquita RA, Guan T, Kleinstein SH, Kaech SM. Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8+ T Cell Terminal Differentiation and Loss of Multipotency. Immunity 2017, 46: 596-608. PMID: 28410989, PMCID: PMC5457165, DOI: 10.1016/j.immuni.2017.03.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesCell DifferentiationChromatinEnhancer of Zeste Homolog 2 ProteinFlow CytometryForkhead Box Protein O1Gene ExpressionHistonesImmunoblottingImmunologic MemoryLysineMethylationMice, Inbred C57BLMice, KnockoutMice, TransgenicModels, ImmunologicalMultipotent Stem CellsPolycomb Repressive Complex 2Reverse Transcriptase Polymerase Chain ReactionConceptsH3K27me3 depositionPolycomb repressive complex 2T cell terminal differentiationRepressive complex 2MP cellsLoss of multipotencyPro-survival genesCell terminal differentiationFate restrictionPermissive chromatinEpigenetic silencingMemory cell potentialDevelopmental plasticityCell developmentTerminal differentiationCell differentiationGenesPrecursor cellsFOXO1 expressionChromatinMemory precursor cellsMultipotencyCell maturationClonal expansionCells
2016
Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection
Bohannon C, Powers R, Satyabhama L, Cui A, Tipton C, Michaeli M, Skountzou I, Mittler RS, Kleinstein SH, Mehr R, Lee FE, Sanz I, Jacob J. Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection. Nature Communications 2016, 7: 11826. PMID: 27270306, PMCID: PMC4899631, DOI: 10.1038/ncomms11826.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAmino Acid MotifsAnimalsAntigensComplementarity Determining RegionsCytidine DeaminaseGerminal CenterImmunityImmunoglobulin Heavy ChainsImmunoglobulin MMice, Inbred C57BLMutationNeutralization TestsOrthomyxoviridaeOrthomyxoviridae InfectionsPlasma CellsSomatic Hypermutation, ImmunoglobulinSpleenConceptsIgM plasma cellsIgG plasma cellsPlasma cellsGerminal centersBone marrowLethal virus challengeProtective host immunitySomatic mutationsActivation-induced cytidine deaminaseHumoral immunityProtective antibodiesVirus challengeLong-term protectionHost immunityB cellsAffinity maturationMarrowLifelong sourceImmunityAntibodiesCellsCytidine deaminaseMutationsReplacement mutationsSpleenIndividual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells
Rubelt F, Bolen CR, McGuire HM, Heiden J, Gadala-Maria D, Levin M, M. Euskirchen G, Mamedov MR, Swan GE, Dekker CL, Cowell LG, Kleinstein SH, Davis MM. Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells. Nature Communications 2016, 7: 11112. PMID: 27005435, PMCID: PMC5191574, DOI: 10.1038/ncomms11112.Peer-Reviewed Original ResearchConceptsChromosome-wide levelJ gene segmentsAntigen receptor repertoireHeritable mechanismsSingle chromosomeEpigenetic differencesHeritable differencesReceptor repertoireLymphocyte receptor repertoireGene segmentsAdaptive immune systemHeritable factorsRepertoireRelative usageAntigen-experienced cellsThymic selectionCellsImmune systemChromosomesSignificant variationCDR3 regionMonozygotic twinsRearrangementT lymphocyte subsets
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 activityProduction of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells
Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, Kaech SM. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells. Nature Immunology 2015, 16: 871-879. PMID: 26147684, PMCID: PMC4713030, DOI: 10.1038/ni.3224.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsCD8-Positive T-LymphocytesDendritic CellsFlow CytometryGene Expression ProfilingHost-Pathogen InteractionsImmunologic MemoryInflammationInterleukin-10Lymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMice, Inbred C57BLMice, KnockoutReverse Transcriptase Polymerase Chain ReactionT-Lymphocytes, RegulatoryLong-lived IgM plasma cells confer host protection against viral challenge (LYM6P.717)
Bohannon C, Powers R, Satyabhama L, Cui A, Tipton C, Michaeli M, Mehr R, Mittler R, Kleinstein S, Sanz I, Jacob J. Long-lived IgM plasma cells confer host protection against viral challenge (LYM6P.717). The Journal Of Immunology 2015, 194: 135.5-135.5. DOI: 10.4049/jimmunol.194.supp.135.5.Peer-Reviewed Original Research
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 Research
2012
NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells
Eisenbarth SC, Williams A, Colegio OR, Meng H, Strowig T, Rongvaux A, Henao-Mejia J, Thaiss CA, Joly S, Gonzalez DG, Xu L, Zenewicz LA, Haberman AM, Elinav E, Kleinstein SH, Sutterwala FS, Flavell RA. NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 2012, 484: 510-513. PMID: 22538615, PMCID: PMC3340615, DOI: 10.1038/nature11012.Peer-Reviewed Original Research
2011
Cell subset prediction for blood genomic studies
Bolen CR, Uduman M, Kleinstein SH. Cell subset prediction for blood genomic studies. BMC Bioinformatics 2011, 12: 258. PMID: 21702940, PMCID: PMC3213685, DOI: 10.1186/1471-2105-12-258.Peer-Reviewed Original ResearchConceptsPeripheral blood mononuclear cellsTotal peripheral blood mononuclear cellsGene signatureSubset-specific genesBlood mononuclear cellsPatient blood samplesPersonalized treatment decisionsSpecific cell subsetsHCV patientsPBMC subsetsNK cellsStandard therapyCell subsetsMononuclear cellsT cellsTreatment decisionsTherapy responseBlood samplesB cellsMyeloid cellsCellular sourceTranscriptional profilingDisease mechanismsGene expression profilesCellsGerminal Center B Cell and T Follicular Helper Cell Development Initiates in the Interfollicular Zone
Kerfoot SM, Yaari G, Patel JR, Johnson KL, Gonzalez DG, Kleinstein SH, Haberman AM. Germinal Center B Cell and T Follicular Helper Cell Development Initiates in the Interfollicular Zone. Immunity 2011, 34: 947-960. PMID: 21636295, PMCID: PMC3280079, DOI: 10.1016/j.immuni.2011.03.024.Peer-Reviewed Original ResearchSomatic hypermutation targeting is influenced by location within the immunoglobulin V region
Cohen RM, Kleinstein SH, Louzoun Y. Somatic hypermutation targeting is influenced by location within the immunoglobulin V region. Molecular Immunology 2011, 48: 1477-1483. PMID: 21592579, PMCID: PMC3109224, DOI: 10.1016/j.molimm.2011.04.002.Peer-Reviewed Original ResearchConceptsObserved mutation patternSpecific DNA motifsBiased codon usageImmunoglobulin V genesMutation accumulationGene positionCodon usageMutation patternsDNA motifsPositive selectionPosition-specific effectsImmunoglobulin V regionsNegative selectionB cellsMutationsMutation frequencyV geneGenesPeripheral B cellsSubstitution typeV regionsTargetingSpecific targetingCellsSequenceInter-follicular germinal center B cell and T follicular helper cell development precedes follicular Tfh maintenance (63.23)
Kerfoot S, Yaari G, Patel J, Johnson K, Gonzalez D, Kleinstein S, Haberman A. Inter-follicular germinal center B cell and T follicular helper cell development precedes follicular Tfh maintenance (63.23). The Journal Of Immunology 2011, 186: 63.23-63.23. DOI: 10.4049/jimmunol.186.supp.63.23.Peer-Reviewed Original ResearchGerminal center B cellsB cellsPD-1T cellsT-cell immigrationFollicular helper cell developmentTfh cell differentiationCognate B cellsDays post immunizationSuch B cellsB cell entryTfh cellsTFH phenotypeInterfollicular zonesPost immunizationGerminal centersBCL-6GL7 expressionCell immigrationLong-term maintenanceCell entryCell developmentFolliclesCell typesCellsActivated germinal centre B cells undergo directed migration.
O'Connor MJ, Hauser AE, Haberman AM, Kleinstein SH. Activated germinal centre B cells undergo directed migration. International Journal Of Data Mining And Bioinformatics 2011, 5: 321-31. PMID: 21805826, PMCID: PMC4343311, DOI: 10.1504/ijdmb.2011.040387.Peer-Reviewed Original Research