2022
Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Unterman A, Sumida TS, Nouri N, Yan X, Zhao AY, Gasque V, Schupp JC, Asashima H, Liu Y, Cosme C, Deng W, Chen M, Raredon MSB, Hoehn KB, Wang G, Wang Z, DeIuliis G, Ravindra NG, Li N, Castaldi C, Wong P, Fournier J, Bermejo S, Sharma L, Casanovas-Massana A, Vogels CBF, Wyllie AL, Grubaugh ND, Melillo A, Meng H, Stein Y, Minasyan M, Mohanty S, Ruff WE, Cohen I, Raddassi K, Niklason L, Ko A, Montgomery R, Farhadian S, Iwasaki A, Shaw A, van Dijk D, Zhao H, Kleinstein S, Hafler D, Kaminski N, Dela Cruz C. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nature Communications 2022, 13: 440. PMID: 35064122, PMCID: PMC8782894, DOI: 10.1038/s41467-021-27716-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAgedAntibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCells, CulturedCOVID-19COVID-19 Drug TreatmentFemaleGene Expression ProfilingGene Expression RegulationHumansImmunity, InnateMaleReceptors, Antigen, B-CellReceptors, Antigen, T-CellRNA-SeqSARS-CoV-2Single-Cell AnalysisConceptsProgressive COVID-19B cell clonesSingle-cell analysisT cellsImmune responseMulti-omics single-cell analysisCOVID-19Cell clonesAdaptive immune interactionsSevere COVID-19Dynamic immune responsesGene expressionSARS-CoV-2 virusAdaptive immune systemSomatic hypermutation frequenciesCellular effectsProtein markersEffector CD8Immune signaturesProgressive diseaseHypermutation frequencyProgressive courseClassical monocytesClonesImmune interactions
2021
Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children
Ramaswamy A, Brodsky NN, Sumida TS, Comi M, Asashima H, Hoehn KB, Li N, Liu Y, Shah A, Ravindra NG, Bishai J, Khan A, Lau W, Sellers B, Bansal N, Guerrerio P, Unterman A, Habet V, Rice AJ, Catanzaro J, Chandnani H, Lopez M, Kaminski N, Dela Cruz CS, Tsang JS, Wang Z, Yan X, Kleinstein SH, van Dijk D, Pierce RW, Hafler DA, Lucas CL. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity 2021, 54: 1083-1095.e7. PMID: 33891889, PMCID: PMC8043654, DOI: 10.1016/j.immuni.2021.04.003.Peer-Reviewed Original ResearchConceptsMIS-C patientsDisease severityInflammatory syndromeTCR repertoireSARS-CoV-2-associated multisystem inflammatory syndromeAsymptomatic SARS-CoV-2 infectionSARS-CoV-2 infectionAdult COVID-19Post-infectious complicationsMultisystem inflammatory syndromeCytotoxicity genesHealthy pediatricImmune dysregulationMemory TActive infectionMyeloid dysfunctionPatientsSingle-cell RNA sequencingFlow cytometrySerum proteomicsRepertoire analysisElevated expressionSeverityAlarminsCOVID-19
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
Individual 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 subsetsCharacterization 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 ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesDiabetes Mellitus, Type 1InsulinIslets of LangerhansMice, Inbred NODMice, TransgenicPrediabetic StateConceptsPrediabetic 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 infectionZEB2CooperateProduction 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, Regulatory
2014
TLR4 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 memory
2013
Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity
Bryniarski K, Ptak W, Jayakumar A, Püllmann K, Caplan MJ, Chairoungdua A, Lu J, Adams BD, Sikora E, Nazimek K, Marquez S, Kleinstein SH, Sangwung P, Iwakiri Y, Delgato E, Redegeld F, Blokhuis BR, Wojcikowski J, Daniel AW, Kormelink T, Askenase PW. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. Journal Of Allergy And Clinical Immunology 2013, 132: 170-181.e9. PMID: 23727037, PMCID: PMC4176620, DOI: 10.1016/j.jaci.2013.04.048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesCD8-Positive T-LymphocytesDermatitis, ContactEpitopesExosomesHumansImmune ToleranceMiceMicroRNAsProtein BiosynthesisT-Lymphocytes, RegulatoryConceptsCutaneous contact sensitivityEffector T cellsT cell toleranceT cellsExosome-like nanovesiclesContact sensitivityCS-effector T cellsMiRNA-150Regulatory T cellsAntigen-specific mannerSuppressor T cellsRole of antibodiesAdoptive cell transfer modelCell transfer modelT cell regulationLight chainSuppressor cellsLymph nodesReactive haptenImmune suppressionMicroRNA-150Systemic injectionAntibody light chainIntravenous injectionSpleen cells