Featured Publications
Maturation of germinal center B cells after influenza virus vaccination in humans
McIntire K, Meng H, Lin T, Kim W, Moore N, Han J, McMahon M, Wang M, Malladi S, Mohammed B, Zhou J, Schmitz A, Hoehn K, Carreño J, Yellin T, Suessen T, Middleton W, Teefey S, Presti R, Krammer F, Turner J, Ward A, Wilson I, Kleinstein S, Ellebedy A. Maturation of germinal center B cells after influenza virus vaccination in humans. Journal Of Experimental Medicine 2024, 221: e20240668. PMID: 38935072, PMCID: PMC11211068, DOI: 10.1084/jem.20240668.Peer-Reviewed Original ResearchConceptsB cellsInfluenza vaccineGerminal centersAntigen-specific GC B cellsResponse to seasonal influenza vaccinationLong-lived bone marrow plasma cellsResponse to influenza vaccinationBone marrow plasma cellsGerminal center B cellsGC B cell clonesInfluenza virus vaccineMaturation of B cellsMarrow plasma cellsSeasonal influenza vaccineMemory B cellsHemagglutinin (HAB cell clonesGC B cellsInfluenza hemagglutinin (HAH5 HANeedle aspirationLymphoid structuresLymph nodesPlasma cellsGC reaction
2021
Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving
Hoehn KB, Turner JS, Miller FI, Jiang R, Pybus OG, Ellebedy A, Kleinstein SH. Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving. ELife 2021, 10: e70873. PMID: 34787567, PMCID: PMC8741214, DOI: 10.7554/elife.70873.Peer-Reviewed Original ResearchMeSH KeywordsB-LymphocytesEvolution, MolecularGerminal CenterHumansInfluenza VaccinesInfluenza, HumanPhylogenyVaccinationConceptsSeasonal influenza vaccinationInfluenza vaccinationB-cell lineageGerminal centersB cell evolutionPoor efficacyB cellsSeasonal influenza virus vaccinationSeasonal influenza virus vaccinesVaccine-induced B cell responsesInfluenza virus vaccinationInfluenza virus vaccinePre-existing immunityB cell responsesMemory B cellsCell lineagesGC B cellsSeasonal vaccinationHIV infectionVirus vaccinationVirus vaccineVaccinationVaccine antigensCell responsesSignificant heterogeneity
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 centreMutant 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
Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation
Austin JW, Buckner CM, Kardava L, Wang W, Zhang X, Melson VA, Swanson RG, Martins AJ, Zhou JQ, Hoehn KB, Fisk JN, Dimopoulos Y, Chassiakos A, O'Dell S, Smelkinson MG, Seamon CA, Kwan RW, Sneller MC, Pittaluga S, Doria-Rose NA, McDermott A, Li Y, Chun TW, Kleinstein SH, Tsang JS, Petrovas C, Moir S. Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation. Science Translational Medicine 2019, 11 PMID: 31776286, PMCID: PMC7479651, DOI: 10.1126/scitranslmed.aax0904.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodies, NeutralizingAntibody AffinityAntigens, CD19B-LymphocytesCytokinesFemaleGerminal CenterHIV InfectionsHumansImmunologic MemoryLymph NodesMaleMiddle AgedMutation RatePhenotypeReceptors, Antigen, B-CellT-Box Domain ProteinsT-Lymphocytes, Helper-InducerTranscriptomeYoung AdultConceptsHIV-specific B cellsT-betGC B cellsGerminal centersB cellsLymph nodesPoor affinity maturationChronic immune activationMemory B cell compartmentAntibody-mediated immunityChronic infectious diseaseOptimal antibody responseB cell compartmentChronic human infectionsB cell receptorHIV viremiaImmunologic outcomesHIV infectionViremic individualsChronic viremiaImmune activationPeripheral bloodProtective antibodiesAntibody responseCD19
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 frequencyMutationsSequenceMotifLong-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 mutationsSpleen
2015
Salmonella 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 microdissection
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
2011
Germinal 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 ResearchMeSH KeywordsAnimalsAntigensB-LymphocytesCell DifferentiationCell MovementGerminal CenterMicePhenotypeT-Lymphocytes, Helper-InducerActivated 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
2009
Taking Advantage: High-Affinity B Cells in the Germinal Center Have Lower Death Rates, but Similar Rates of Division, Compared to Low-Affinity Cells
Anderson SM, Khalil A, Uduman M, Hershberg U, Louzoun Y, Haberman AM, Kleinstein SH, Shlomchik MJ. Taking Advantage: High-Affinity B Cells in the Germinal Center Have Lower Death Rates, but Similar Rates of Division, Compared to Low-Affinity Cells. The Journal Of Immunology 2009, 183: 7314-7325. PMID: 19917681, PMCID: PMC4106706, DOI: 10.4049/jimmunol.0902452.Peer-Reviewed Original ResearchConceptsLow-affinity B cellsLow-affinity cellsGerminal centersB cellsHigh-affinity B cellsHigh-affinity cellsDeath rateHigh death rateLower death ratesImmune responseHigh-affinity AbsB lymphocytesMemory responsesExtracellular pathogensSame AgPrimary responseGC reactionProliferative advantageSimilar ratesSurvivalCellsCell cycleControl of survivalHigh affinityResponse
2007
Definition of Germinal-Center B Cell Migration In Vivo Reveals Predominant Intrazonal Circulation Patterns
Hauser AE, Junt T, Mempel TR, Sneddon MW, Kleinstein SH, Henrickson SE, von Andrian UH, Shlomchik MJ, Haberman AM. Definition of Germinal-Center B Cell Migration In Vivo Reveals Predominant Intrazonal Circulation Patterns. Immunity 2007, 26: 655-667. PMID: 17509908, DOI: 10.1016/j.immuni.2007.04.008.Peer-Reviewed Original Research
2003
Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center
Kleinstein SH, Singh JP. Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center. International Immunology 2003, 15: 871-884. PMID: 12807826, DOI: 10.1093/intimm/dxg085.sgm.Peer-Reviewed Original Research
2001
Toward Quantitative Simulation of Germinal Center Dynamics: Biological and Modeling Insights from Experimental Validation
KLEINSTEIN S, SINGH J. Toward Quantitative Simulation of Germinal Center Dynamics: Biological and Modeling Insights from Experimental Validation. Journal Of Theoretical Biology 2001, 211: 253-275. PMID: 11444956, DOI: 10.1006/jtbi.2001.2344.Peer-Reviewed Original ResearchConceptsCenter dynamicsParticular mathematical modelOrdinary differential equationsGerminal center dynamicsImmune system dynamicsDifferential equationsExperimental dataMathematical modelStochastic frameworkAverage dynamicsSpecific experimental dataDeterministic modelSystem dynamicsModel parametersPossible extensionsGeneral methodologyQuantitative simulationOpreaNew implementationDynamicsModeling insightsPerelsonCenter behaviorEquationsExperimental validation