Hao Yuan Kueh, PhD
Associate Professor TenureDownloadHi-Res Photo
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Immunobiology
Primary
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Yale Center for Systems and Engineering Immunology (CSEI)
100 College St, Rm 1152
New Haven, CT 06511
United States
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Associate Professor Tenure
Biography
The Kueh Lab seeks to elucidate the molecular circuitry controlling immune cell development and function, and to leverage these principles to engineer next-generation immune cell therapies. Our goal is to build a quantitative, biophysical understanding of immune cell circuit dynamics and design, enabling us to reprogram these circuits in a robust and controllable manner.
To meet this challenge, we measure, manipulate, and model the dynamic behavior of immune cell circuits both in vitro and in animal models, using approaches that are quantitative, single-cell resolved, and high-throughput. These include live-cell imaging, single-cell genomics, and pooled screening strategies. We also apply synthetic biology to construct and rewire immune control circuits, with the aim of equipping immune cells with novel or enhanced functional and therapeutic capabilities.
Last Updated on September 27, 2025.
Appointments
Immunobiology
Associate Professor TenurePrimary
Other Departments & Organizations
Education & Training
- Postdoctoral Scholar
- California Institute of Technology (2016)
- PhD
- Harvard University, Biophysics (2008)
- AB
- Princeton University, Physics (2002)
Research
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Overview
Medical Research Interests
Adaptive Immunity; Computational Biology; Hematopoietic Stem Cells; Immunity, Innate; Immunologic Memory; Lymphoid Progenitor Cells; Myeloid Progenitor Cells
Public Health Interests
Cancer; Genetics, Genomics, Epigenetics; Immunology
ORCID
0000-0001-6272-6673
Publications
Featured Publications
Proofreading and single-molecule sensitivity in T cell receptor signaling by condensate nucleation
White W, Yirdaw H, Ben-Sasson A, Groves J, Baker D, Kueh H. Proofreading and single-molecule sensitivity in T cell receptor signaling by condensate nucleation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2422787122. PMID: 40445763, PMCID: PMC12146730, DOI: 10.1073/pnas.2422787122.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsKinetic proofreadingSignaling pathwayT cell receptor signalingTCR signaling pathwayLAT condensatesHigh-affinity peptidesTCR pathwayMajor histocompatibility complexSingle-molecule sensitivityProofreadingReceptor signalingForeign peptidesBinding eventsBiochemical mechanismsActivation of T cellsSignaling propertiesPathwayHistocompatibility complexTarget cellsT cellsPeptideCondensation nucleationSignalPhosphorylationPMHC ligandsReversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision
Abadie K, Clark E, Valanparambil R, Ukogu O, Yang W, Daza R, Ng K, Fathima J, Wang A, Lee J, Nasti T, Bhandoola A, Nourmohammad A, Ahmed R, Shendure J, Cao J, Kueh H. Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision. Immunity 2024, 57: 271-286.e13. PMID: 38301652, PMCID: PMC10922671, DOI: 10.1016/j.immuni.2023.12.006.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsT cellsCD8+ T cellsMemory T cell numbersT cell numbersOptimal immune responseImmune response magnitudeMemory potentialAcute infection modelResponse to stimulationImmune responseAntigen recognitionSelf-RenewalInfection modelPathogen clearanceMemory regulationCell numberEpigenetic silencingTCF1Response magnitudeCellsAntigen perception in T cells by long-term Erk and NFAT signaling dynamics
Wither M, White W, Pendyala S, Leanza P, Fowler D, Kueh H. Antigen perception in T cells by long-term Erk and NFAT signaling dynamics. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2308366120. PMID: 38113261, PMCID: PMC10756264, DOI: 10.1073/pnas.2308366120.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsPeptide-major histocompatibility complexT cell abilitySignaling DynamicsT cellsT cell responsesReporter mouse strainGene regulationTranscriptional responseLive T cellsQuantitative imaging assaysImaging assayMouse strainsNFAT pathwayCombinatorial mechanismsERKHistocompatibility complexNFATAntigenDetection hingesPathwayUnsupervised discovery of dynamic cell phenotypic states from transmitted light movies
Nguyen P, Chien S, Dai J, Monnat R, Becker P, Kueh H. Unsupervised discovery of dynamic cell phenotypic states from transmitted light movies. PLOS Computational Biology 2021, 17: e1009626. PMID: 34968384, PMCID: PMC8754342, DOI: 10.1371/journal.pcbi.1009626.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsCell's phenotypic statePhenotypic statesLatent cell representationsPatient-derived acute myeloid leukemia cellsSingle-cell analysis methodsMyeloid leukemia cellsAcute myeloid leukemia cellsPhenotypic readoutsBlood cell typesModern biologyCell statesMorphological readoutsLeukemia cellsCell typesRate inferenceMorphological stateBiologyVariational auto-encoder architectureCellsHeterogeneous populationStem-cellIdentificationTransition ratesState heterogeneityTunable, division-independent control of gene activation timing by a polycomb switch
Pease N, Nguyen P, Woodworth M, Ng K, Irwin B, Vaughan J, Kueh H. Tunable, division-independent control of gene activation timing by a polycomb switch. Cell Reports 2021, 34: 108888. PMID: 33761349, PMCID: PMC8024876, DOI: 10.1016/j.celrep.2021.108888.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsEpigenetic switchHistone H3 lysine-27 trimethylationCell generationMultiple cell generationsChromatin modifiersRepression mechanismGene Bcl11bPopulation size controlTranscription factorsCell divisionH3K27me3 levelsDemethylase activitySilent stateInactive stateLociH3K27me3BCL11BActive stateCellsChromatinHistoneDemethylaseMethyltransferaseSize controlGenes
2025
Design of a potent interleukin-21 mimic for cancer immunotherapy
Chun J, Lim B, Roy S, Walsh M, Abhiraman G, Zhangxu K, Atajanova T, Revach O, Clark E, Li P, Palin C, Khanna A, Tower S, Kureshi R, Hoffman M, Sharova T, Lawless A, Cohen S, Boland G, Nguyen T, Peprah F, Tello J, Liu S, Kim C, Shin H, Quijano-Rubio A, Jude K, Gerben S, Murray A, Heine P, DeWitt M, Ulge U, Carter L, King N, Silva D, Kueh H, Kalia V, Sarkar S, Jenkins R, Garcia K, Leonard W, Dougan M, Dougan S, Baker D. Design of a potent interleukin-21 mimic for cancer immunotherapy. Science Immunology 2025, 10: eadx1582. PMID: 41004565, DOI: 10.1126/sciimmunol.adx1582.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsRegulatory T cellsCytotoxic T cellsT cellsIL-21Cancer immunotherapyGoal of cancer immunotherapyAntitumor activityExpression of IFN-gAntitumor T cellsAntitumor responseTNF blockadeTumor antigensAntidrug antibodiesAntitumor efficacyGranzyme BInterleukin-21IFN-gTumor modelTranslational potentialImmunotherapyAntitumorDe novoProlonged signalingCross-reactivitySignaling potencyAn early precursor CD8+ T cell that adapts to acute or chronic viral infection
McManus D, Valanparambil R, Medina C, Scharer C, McGuire D, Sobierajska E, Hu Y, Chang D, Wieland A, Lee J, Nasti T, Hashimoto M, Ross J, Prokhnevska N, Cardenas M, Gill A, Clark E, Abadie K, Kumar A, Kaye J, Au-Yeung B, Kueh H, Kissick H, Ahmed R. An early precursor CD8+ T cell that adapts to acute or chronic viral infection. Nature 2025, 640: 772-781. PMID: 39778710, DOI: 10.1038/s41586-024-08562-y.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAcute DiseaseAdoptive TransferAnimalsCD8-Positive T-LymphocytesCell DifferentiationChronic DiseaseDisease Models, AnimalFemaleHepatocyte Nuclear Factor 1-alphaImmunologic MemoryLymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMaleMiceMice, Inbred C57BLPersistent InfectionProgrammed Cell Death 1 ReceptorConceptsStem-like CD8+ T cellsCD8+ T cellsChronic viral infectionsLymphocytic choriomeningitis virusT cellsChronically infected miceInfected micePD-1Viral infectionChronic infectionCentral memory CD8+ T cellsMemory CD8+ T cellsMouse modelReciprocal adoptive transfer experimentsChronic lymphocytic choriomeningitis virusChronic LCMV infectionPD-1 therapyT cell immunityAdoptive transfer experimentsChronic antigenic stimulationStem-like phenotypeLCMV infectionViral clearanceAntigenic stimulationCD8
2024
A timed epigenetic switch balances T and ILC lineage proportions in the thymus
Pease N, Denecke K, Chen L, Gerges P, Kueh H. A timed epigenetic switch balances T and ILC lineage proportions in the thymus. Development 2024, 151: dev203016. PMID: 39655434, PMCID: PMC11664168, DOI: 10.1242/dev.203016.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsEpigenetic switchInnate lymphoid cellsTranscription factor PLZFCell type numberT cell commitmentGene locusMultiple cell typesTranscription factorsLineage decisionsInnate lymphoid cell lineageDevelopmental biologyBCL11BLineagesGenesCell typesPLZFT cellsInnate lymphoid cell progenitorsMultipotent progenitorsT cell outputCellsProgenitorsUpregulationLociLymphoid cells
2021
Scalable control of developmental timetables by epigenetic switching networks
Nguyen P, Pease N, Kueh H. Scalable control of developmental timetables by epigenetic switching networks. Journal Of The Royal Society Interface 2021, 18: 20210109. PMID: 34283940, PMCID: PMC8292019, DOI: 10.1098/rsif.2021.0109.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsEpigenetic switchRegulatory networksDynamics of gene regulatory networksOrgan sizeGene regulatory networksTiming of developmental eventsRegulatory gene locusCell generationGene locusLineage specificationPopulation sizeDevelopmental eventsGeneration of differentiated cellsGenesCellsLociActivation stepMultiplexed single-cell profiling of chromatin states at genomic loci by expansion microscopy
Woodworth M, Ng K, Halpern A, Pease N, Nguyen P, Kueh H, Vaughan J. Multiplexed single-cell profiling of chromatin states at genomic loci by expansion microscopy. Nucleic Acids Research 2021, 49: e82-e82. PMID: 34048564, PMCID: PMC8373070, DOI: 10.1093/nar/gkab423.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsHistone modificationsGenomic lociChromatin stateNon-repetitive genomic regionsRegulation of genome architectureRNA polymerase II loadingFunction of multicellular organismsMultiple histone modificationsDevelopmentally-regulated genesHistone modification levelsPopulation-averaged measurementsExpansion microscopySingle cellsGenome architectureGenomic regionsHistone marksMulticellular organismsIndividual lociEpigenetic stateHousekeeping genesGene locusLociHistoneModification levelsGenes
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Yale Center for Systems and Engineering Immunology (CSEI)
100 College St, Rm 1152
New Haven, CT 06511
United States