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 protectionMind the gap from research laboratory to clinic: Challenges and opportunities for next-generation assays in human diseases
D'Souza MP, Palin AC, Calder T, Golding H, Kleinstein SH, Milliken EL, O'Connor D, Tomaras G, Warren J, Boggiano C. Mind the gap from research laboratory to clinic: Challenges and opportunities for next-generation assays in human diseases. Vaccine 2021, 39: 5233-5239. PMID: 34366145, PMCID: PMC8343370, DOI: 10.1016/j.vaccine.2021.07.071.Peer-Reviewed Original ResearchConceptsNext-generation assaysSevere acute respiratory syndrome coronavirus type 2Human immunodeficiency virusCoronavirus type 2National InstituteVaccine delivery methodNovel animal modelProtective immunityImmunodeficiency virusLicensed vaccineEffective vaccineModern vaccinologyPowerful adjuvantAnimal modelsImproved vaccinesType 2Immune systemImmunogen designVaccine developmentInfectious diseasesVaccineGeneration assaysTuberculosisDiseaseCritical pathogensHeterogeneity 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
CD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response
Lu Y, Jiang R, Freyn AW, Wang J, Strohmeier S, Lederer K, Locci M, Zhao H, Angeletti D, O’Connor K, Kleinstein SH, Nachbagauer R, Craft J. CD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response. Journal Of Experimental Medicine 2020, 218: e20200547. PMID: 33326020, PMCID: PMC7748821, DOI: 10.1084/jem.20200547.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody FormationAntigensB-LymphocytesCD4 AntigensDisease Models, AnimalEpitopesForkhead Transcription FactorsGerminal CenterHumansImmunityImmunologic MemoryInfluenza, HumanInfluenzavirus BIntegrasesMice, Inbred C57BLOrthomyxoviridae InfectionsReceptors, Antigen, B-CellSpecies SpecificityT-Lymphocytes, RegulatoryVaccinationConceptsB cell responsesGerminal center B cell responsesFollicular regulatory T cellsRegulatory T cellsTfr cellsCell responsesT cellsViral challengeHumoral memoryVirus-specific B cell responsesAntigen-specific B cell responsesFollicular helper T cellsHA stalk regionHelper T cellsInfluenza virus infectionGerminal center developmentAntibody responsePlasma cellsVirus infectionImmunization modelAntibody productionBCR repertoireInfluenza virusRepeated exposureInfluenza virus glycoproteinsHuman 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
Adaptive Immune Receptor Repertoire Community recommendations for sharing immune-repertoire sequencing data
Rubelt F, Busse CE, Bukhari SAC, Bürckert JP, Mariotti-Ferrandiz E, Cowell LG, Watson CT, Marthandan N, Faison WJ, Hershberg U, Laserson U, Corrie BD, Davis MM, Peters B, Lefranc MP, Scott JK, Breden F, Luning Prak E, Kleinstein S. Adaptive Immune Receptor Repertoire Community recommendations for sharing immune-repertoire sequencing data. Nature Immunology 2017, 18: 1274-1278. PMID: 29144493, PMCID: PMC5790180, DOI: 10.1038/ni.3873.Peer-Reviewed Original ResearchInterleukin-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 1Polycomb 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
Solving Immunology?
Vodovotz Y, Xia A, Read EL, Bassaganya-Riera J, Hafler DA, Sontag E, Wang J, Tsang JS, Day JD, Kleinstein SH, Butte AJ, Altman MC, Hammond R, Sealfon SC. Solving Immunology? Trends In Immunology 2016, 38: 116-127. PMID: 27986392, PMCID: PMC5695553, DOI: 10.1016/j.it.2016.11.006.Peer-Reviewed Original ResearchA 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 contributionLong-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 mutationsSpleenAge‐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-2Characterization of Diabetogenic CD8+ T Cells IMMUNE THERAPY WITH METABOLIC BLOCKADE*
Garyu JW, Uduman M, Stewart A, Rui J, Deng S, Shenson J, Staron MM, Kaech SM, Kleinstein SH, Herold KC. Characterization of Diabetogenic CD8+ T Cells IMMUNE THERAPY WITH METABOLIC BLOCKADE*. Journal Of Biological Chemistry 2016, 291: 11230-11240. PMID: 26994137, PMCID: PMC4900270, DOI: 10.1074/jbc.m115.713362.Peer-Reviewed Original ResearchConceptsPrediabetic NOD miceNOD miceT cellsDiabetogenic CD8Reactive cellsMemory precursor effector cellsType 1 diabetes mellitusΒ-cellsGlucose tolerance deterioratesAutoreactive T cellsHyperglycemic NOD miceInsulin-producing β-cellsAutoimmune effectorsAutoimmune diabetesReactive CD8Glucose intoleranceDiabetes mellitusEffector cellsImmune therapyMetabolic disturbancesTolerance deterioratesDisease progressionInsulin pelletsSubset of cellsConventional antigens
2015
The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection
Dominguez CX, Amezquita RA, Guan T, Marshall HD, Joshi NS, Kleinstein SH, Kaech SM. The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. Journal Of Experimental Medicine 2015, 212: 2041-2056. PMID: 26503446, PMCID: PMC4647261, DOI: 10.1084/jem.20150186.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesCell DifferentiationCluster AnalysisFlow CytometryHomeodomain ProteinsHost-Pathogen InteractionsLectins, C-TypeLymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMice, Inbred C57BLMice, KnockoutMice, TransgenicOligonucleotide Array Sequence AnalysisProtein BindingReceptors, ImmunologicRepressor ProteinsReverse Transcriptase Polymerase Chain ReactionT-Box Domain ProteinsT-Lymphocytes, CytotoxicTranscriptomeZinc Finger E-box Binding Homeobox 2ConceptsTerminal differentiationT cell terminal differentiationChromatin immunoprecipitation sequencingNovel genetic pathwaysTranscription factor ZEB2Cell terminal differentiationZeb2 functionImmunoprecipitation sequencingMemory cell potentialDifferentiation programGenetic pathwaysCytotoxic T lymphocyte differentiationTerminal effectorZEB2 mRNAPrecursor cellsCoordinated actionLymphocyte differentiationT lymphocyte differentiationMemory precursor cellsGenesT-betDifferentiationViral infectionZEB2Cooperate