2025
Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA–directed autoimmunity in mouse and human
Gronke K, Nguyen M, Fuhrmann H, Santamaria de Souza N, Schumacher J, Pereira M, Löschberger U, Brinkhege A, Becker N, Yang Y, Sonnert N, Leopold S, Martin A, von Münchow-Klein L, Pessoa Rodrigues C, Cansever D, Hallet R, Richter K, Schubert D, Daniel G, Dylus D, Forkel M, Schwinge D, Schramm C, Redanz S, Lassen K, Manfredo Vieira S, Piali L, Palm N, Bieniossek C, Kriegel M. Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA–directed autoimmunity in mouse and human. Science Translational Medicine 2025, 17: eadj6294. PMID: 39908347, DOI: 10.1126/scitranslmed.adj6294.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusAutoimmune diseasesToll-like receptor 8Gut pathobiontsHuman adaptive immune responseLong-term sequelaeAdaptive immune responsesHuman T cellsChronic autoimmune diseaseHuman monocyte activationContribution to autoimmunityAutoimmune hepatitisAutoantibody titersAnti-<i>E.Autoimmune pathophysiologyLupus modelT-helperLifelong immunosuppressionTargeted therapyT cellsDisease activityLupus erythematosusAutoantibody responseMonocyte activationImmune response
2024
Mis-Splicing Derived Neoantigens and Cognate T Cell Receptors in Splicing Factor Mutant Myeloid Neoplasms
Kim W, Crosse E, De Neef E, Etxeberria I, Sabio E, Wang E, Bewersdorf J, Lu S, Belleville A, Fox N, Castro C, Zhang P, Fujino T, Lewis J, Rahman J, Zhang B, Winick J, Lewis A, Stanley R, Dewolf S, Meskauskaite Urben B, Takizawa M, Krause T, Molina H, Chaligne R, Koppikar P, Molldrem J, Gigoux M, Merghoub T, Daniyan A, Greenbaum B, Klebanoff C, Bradley R, Abdel-Wahab O. Mis-Splicing Derived Neoantigens and Cognate T Cell Receptors in Splicing Factor Mutant Myeloid Neoplasms. Blood 2024, 144: 343-343. DOI: 10.1182/blood-2024-198639.Peer-Reviewed Original ResearchCD8+ T cellsT cell receptorPrimary human T cellsHuman T cellsT cellsHLA-ILeukemic cellsSRSF2 mutationsHealthy donorsIsolated CD8+ T cellsGraft-versus-leukemia effectT cell cytotoxic functionTCR-T cell therapyVirus-reactive T cellsAllogeneic stem cell transplantationT cell-based immunotherapyT cell receptor clonotypesLyse leukemic cellsPatient PBMC samplesCognate T cell receptorsDonor T cellsHigh-risk MDSStem cell transplantationHLA class IMis-splicingDOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells.
Williams A, Siniscalco E, Grassmann J, Craft J, Eisenbarth S, Uthaman G. DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells. The Journal Of Immunology 2024, 212: 0620_4120-0620_4120. DOI: 10.4049/jimmunol.212.supp.0620.4120.Peer-Reviewed Original ResearchPeanut-specific IgET cellsSpecific IgEFood allergyT Follicular Helper CellsCD4+ T cellsDOCK8-deficient patientsFood-specific IgEPeanut-specific IgE.Human T cellsCells in vitroDifferentiation in vivoSevere food allergyTfh cellsRegulatory populationsOvercome toleranceHelper cellsDeficient patientsSpecific IgE.DOCK8IgE productionSTAT3 mutationsMiceCholera toxinIgEThe FLRT3-UNC5B Pathway is a Novel Regulator of T Immunosurveillance
Flies D, Yan C, Yang Q, Arbitman S, Fitzgerald D, Sharee S, Shaik J, Bosiacki J, Myers K, Paucarmayta A, Johnson D, O'Neill T, Cusumano Z, Langermann S, Langenau D, Patel S. The FLRT3-UNC5B Pathway is a Novel Regulator of T Immunosurveillance. The Journal Of Immunology 2024, 212: 0298_5492-0298_5492. DOI: 10.4049/jimmunol.212.supp.0298.5492.Peer-Reviewed Original ResearchT cell activationT cellsCell-derived xenograftsTumor growthT cell anti-tumor immunityInhibitor of T cell activationCell-derived xenograft modelControl T cell responsesHuman T cell functionT cell checkpointsAnti-tumor immunityT cell responsesT cell functionActivated T cellsTumor-immune interactionsPromote tumor growthHuman T cellsCAR-TUNC-5 netrin receptor BZebrafish tumor modelTumor cellsTumor modelReceptor BGain-of-function screenMonoclonal antibodiesThe FLRT3-UNC5B checkpoint pathway inhibits T cell–based cancer immunotherapies
Prajapati K, Yan C, Yang Q, Arbitman S, Fitzgerald D, Sharee S, Shaik J, Bosiacki J, Myers K, Paucarmayta A, Johnson D, O’Neill T, Kundu S, Cusumano Z, Langermann S, Langenau D, Patel S, Flies D. The FLRT3-UNC5B checkpoint pathway inhibits T cell–based cancer immunotherapies. Science Advances 2024, 10: eadj4698. PMID: 38427724, PMCID: PMC10906930, DOI: 10.1126/sciadv.adj4698.Peer-Reviewed Original ResearchConceptsFibronectin leucine-rich transmembrane protein 3T cellsHuman T cellsCancer immunotherapyT cell-based cancer immunotherapyInhibit T cell activationT cell checkpointsActivated human T cellsT cell immunityT cell killingT cell activationHuman cancer modelsImmune-dependent mannerAxon guidance proteinsTarget such mechanismsCAR-TCoinhibitory receptorsGuidance proteinsTumor immunityClinical benefitCancer modelsTumor growthCancer cellsHuman cancersMonoclonal antibodiesThiazolidinedione enhances the efficacy of anti-PD-1 monoclonal antibody in murine melanoma
Zhang X, Gao Y, Tang K, Li Z, Halberstam A, Zhou L, Perry R. Thiazolidinedione enhances the efficacy of anti-PD-1 monoclonal antibody in murine melanoma. AJP Endocrinology And Metabolism 2024, 326: e341-e350. PMID: 38294697, PMCID: PMC11901343, DOI: 10.1152/ajpendo.00346.2023.Peer-Reviewed Original ResearchPD-1 expressionCD8+ T cellsT cell exhaustionPD-1T cellsImmunotherapy efficacyAnti-programmed cell death protein 1Tumor-infiltrating CD8+ T cellsAnti-PD-1 monoclonal antibodyAnti-PD-1 responseAnti-PD-1 treatmentCell death protein 1Enhance immunotherapy efficacyEnhance immunotherapy responseImprove immunotherapy efficacyEfficacy of immunotherapyMurine melanoma modelTumor-bearing miceExpression of peroxisome proliferator-activated receptor gammaOverall survival timePeroxisome proliferator-activated receptor gammaEffect of obesityProliferator-activated receptor gammaHuman T cellsTreated in vitro
2023
Ultrasensitive quantification of HIV-1 cell-to-cell transmission in primary human CD4+ T cells measures viral sensitivity to broadly neutralizing antibodies
Mazurov D, Herschhorn A. Ultrasensitive quantification of HIV-1 cell-to-cell transmission in primary human CD4+ T cells measures viral sensitivity to broadly neutralizing antibodies. MBio 2023, 15: e02428-23. PMID: 38063394, PMCID: PMC10790777, DOI: 10.1128/mbio.02428-23.Peer-Reviewed Original ResearchConceptsHIV-1 cell-to-cell transmissionCell-to-cell transmissionHIV-1Neutralizing antibodiesHIV-1 escapeHIV-1 transmissionHIV-1 resistanceHuman T cellsT cellsClinical trialsMode of transmissionViral sensitivityUltrasensitive assayEvaluation of pre-existingAntibodiesAssayCellsPre-existingRetrovirusesTrialsExploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells
Behrens R, Rajashekar J, Bruce J, Evans E, Hansen A, Salazar-Quiroz N, Simons L, Ahlquist P, Hultquist J, Kumar P, Sherer N. Exploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells. MBio 2023, 14: e00420-23. PMID: 37676006, PMCID: PMC10653828, DOI: 10.1128/mbio.00420-23.Peer-Reviewed Original ResearchConceptsCyclin T1Species-specific differencesViral gene expressionGene expressionHost proteinsIntron-containing viral RNAsBroad-spectrum resistanceHost cell biologyCRISPR/Cas9 geneLatency reversal agentsIsogenic cell linesHuman T cellsEfficient HIV-1 transcriptionHIV-1 gene expressionCell linesViral RNA transcriptionT cellsSpecies-specific regionsCell-intrinsic defectHIV-1 virion productionHousekeeping proteinsNuclear exportRNA transcriptionCell biologyCas9 geneIL-6 trans-signaling in a humanized mouse model of scleroderma
Odell I, Agrawal K, Sefik E, Odell A, Caves E, Kirkiles-Smith N, Horsley V, Hinchcliff M, Pober J, Kluger Y, Flavell R. IL-6 trans-signaling in a humanized mouse model of scleroderma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2306965120. PMID: 37669366, PMCID: PMC10500188, DOI: 10.1073/pnas.2306965120.Peer-Reviewed Original ResearchConceptsBone marrow-derived immune cellsIL-6Human hematopoietic stem cellsImmune cellsT cellsScleroderma skinSoluble IL-6 receptorCD8 T cellsHumanized mouse modelPathogenesis of sclerodermaMesenchymal cellsFibroblast-derived IL-6IL-6 receptorIL-6 signalingT cell activationHuman IL-6Human T cellsExpression of collagenFibrosis improvementPansclerotic morpheaHuman endothelial cellsHumanized miceReduced markersSkin graftsHuman CD4CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis
Xu X, Dennett P, Zhang J, Sherrard A, Zhao Y, Masubuchi T, Bui J, Chen X, Hui E. CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis. Journal Of Experimental Medicine 2023, 220: e20221391. PMID: 37042938, PMCID: PMC10103642, DOI: 10.1084/jem.20221391.Peer-Reviewed Original ResearchConceptsT cellsMajor histocompatibility complexB7 ligandsHuman regulatory T cellsRegulatory T cellsSurface of T cellsCD28 costimulatory signalsAntigen-presenting-cellsAdaptive immune responsesHuman T cellsT cell coreceptorsCostimulatory signalsLigands CD80CTLA4Cell-intrinsicImmune responseCD28Histocompatibility complexTrogocytosisCD28:B7TregsCD80CD86Extrinsic functionsBlockade
2022
HSV-2 increases replication of HIV in human T cells
Pierce C, Preston-Hurlburt P, Loh L, Steach H, Sidoli S, Zhang F, Philbrick W, Nassar M, Krishnaswamy S, Herold K, Herold B. HSV-2 increases replication of HIV in human T cells. The Journal Of Immunology 2022, 208: 182.40-182.40. DOI: 10.4049/jimmunol.208.supp.182.40.Peer-Reviewed Original ResearchCD4 cellsHSV-2HIV reactivationHIV PVLT cellsHerpes simplex virus 2 infectionLncRNA MALAT1Simplex virus 2 infectionHIV-LTR expressionHSV-2 lesionsMALAT1 gene expressionUninfected CD4 cellsFollicular helper cellsHSV-2 infectionCD4 T cellsHIV restriction factorsVirus 2 infectionGlobal HIV epidemicHSV-2 glycoprotein BHIV latent reservoirHuman T cellsInterferon response genesMucosal responsesHSV infectionLatent reservoirType I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells
Sumida TS, Dulberg S, Schupp JC, Lincoln MR, Stillwell HA, Axisa PP, Comi M, Unterman A, Kaminski N, Madi A, Kuchroo VK, Hafler DA. Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells. Nature Immunology 2022, 23: 632-642. PMID: 35301508, PMCID: PMC8989655, DOI: 10.1038/s41590-022-01152-y.Peer-Reviewed Original ResearchConceptsCoinhibitory receptor expressionHuman T cellsIFN-I responsesCoinhibitory receptorsT cellsTIGIT expressionReceptor expressionAcute SARS-CoV-2 infectionPD-1/TimSARS-CoV-2 infectionEnhancement of immunotherapyType 1 interferonT-cell featuresLAG-3Infectious diseasesDifferent temporal kineticsTranscription factorsCancer therapyReceptorsCell featuresKey transcription factorIFNPresent studyMRNA profilingKey regulator
2020
The receptor for advanced glycation endproducts (RAGE) modulates T cell signaling
Reed JC, Preston-Hurlburt P, Philbrick W, Betancur G, Korah M, Lucas C, Herold KC. The receptor for advanced glycation endproducts (RAGE) modulates T cell signaling. PLOS ONE 2020, 15: e0236921. PMID: 32986722, PMCID: PMC7521722, DOI: 10.1371/journal.pone.0236921.Peer-Reviewed Original ResearchConceptsT cellsAdvanced glycation endproductsRAGE expressionGlycation endproductsType 1 diabetes mellitusLess IL-2T cell reactivityT-cell phenotypeHealthy control subjectsIL-2 productionT cell receptorPhosphorylation of ZAP70Human T cellsDiabetes mellitusAutoimmune diseasesJurkat cellsCell reactivityControl subjectsInflammatory productsIL-2Primary CD4T cell signalingCell receptorPatientsCell phenotypeUse of CART cells to selectively target autoantigen-specific T cells for the treatment of autoimmune diabetes
Yu H, Bettini M, Ellis G, Riley J, Collins J, Preston-Hurlburt P, Korah M, Mallone R, Deng S, Wang X, Fremont D, Spiegel D, Cresswell P, Herold K. Use of CART cells to selectively target autoantigen-specific T cells for the treatment of autoimmune diabetes. The Journal Of Immunology 2020, 204: 238.8-238.8. DOI: 10.4049/jimmunol.204.supp.238.8.Peer-Reviewed Original ResearchCART cellsT cellsAutoimmune diabetesCAR constructsHuman antigen-specific CD8Autoantigen-specific T cellsAntigen-specific CD8Pathogenic T cellsPrevious clinical trialsΒ-cell damageChimeric antigen receptorNon-specific actionT cell linesHuman T cellsDominant cell typeHuman insulitisPathogenic subpopulationsNovel immunotherapiesPrimary human T cellsClinical trialsPrimary mediatorPeptide epitopesAntigen receptorMicroglobulin complexCAR signaling
2018
Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection
Lim S, Kirkiles-Smith NC, Pober JS, Bothwell ALM, Choi JM. Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection. Biomaterials 2018, 183: 128-138. PMID: 30165256, PMCID: PMC6141312, DOI: 10.1016/j.biomaterials.2018.08.049.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell ProliferationCell-Penetrating PeptidesCTLA-4 AntigenCytokinesEndothelial CellsFemaleGraft RejectionHuman Umbilical Vein Endothelial CellsHumansLymphocyte ActivationMice, Inbred BALB CMice, KnockoutMice, SCIDMicrovesselsReceptors, ChemokineSkinSkin TransplantationT-LymphocytesConceptsT cell responsesHuman T cell responsesT cell infiltrationHuman T cellsT cellsCell responsesGraft rejectionCell infiltrationSCID/beige miceCell-permeable peptideBlood cytokine levelsT cell alloresponsesCD8 T cellsChemokine receptor expressionGranzyme B expressionAlloreactive T cellsSignificant side effectsDouble knockout miceHuman T cell activationBcl-2-transduced human umbilical vein endothelial cellsT cell activationHuman umbilical vein endothelial cellsUmbilical vein endothelial cellsSystemic immunosuppressantsAllograft rejectionRegulation of C-C chemokine receptor 5 (CCR5) stability by Lys197 and by transmembrane protein aptamers that target it for lysosomal degradation
Petti LM, Marlatt SA, Luo Y, Scheideman EH, Shelar A, DiMaio D. Regulation of C-C chemokine receptor 5 (CCR5) stability by Lys197 and by transmembrane protein aptamers that target it for lysosomal degradation. Journal Of Biological Chemistry 2018, 293: 8787-8801. PMID: 29678881, PMCID: PMC5995508, DOI: 10.1074/jbc.ra117.001067.Peer-Reviewed Original ResearchConceptsG protein-coupled receptorsC motif chemokine receptor 5Transmembrane helicesAmino acidsProtein aptamerFifth transmembrane helixUncharged amino acidsSpecific amino acidsProtein-coupled receptorsSubstitution of LysTraptamersReceptor stabilityLysosomal degradationHomologous positionsDiverse mechanismsChemokine receptor 5Initial characterizationNew therapeutic approachesHuman T cellsStable complexesCCR5 expressionCentral roleNew insightsChemokine receptorsHelix
2016
ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells
Boddupalli CS, Nair S, Gray SM, Nowyhed HN, Verma R, Gibson JA, Abraham C, Narayan D, Vasquez J, Hedrick CC, Flavell RA, Dhodapkar KM, Kaech SM, Dhodapkar MV. ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells. Journal Of Clinical Investigation 2016, 126: 3905-3916. PMID: 27617863, PMCID: PMC5096804, DOI: 10.1172/jci85329.Peer-Reviewed Original ResearchConceptsTissue-resident memory T cellsMemory T cellsT cellsTRM cellsCellular therapyAdoptive cellular therapyImmune-deficient micePotential cellular therapySP T cellsSide population cellsHuman T cellsPutative subsetsAdoptive transferDistinct gene expression profilesCell mobilizationImmune surveillanceQuiescent subsetPopulation cellsMiceTherapyQuiescent phenotypeDistinct subsetsMember 1Nuclear receptorsSignature genesImprovements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary
Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC, Casares S, Garcia JV, Hasenkrug KJ, Kashanchi F, Kitchen SG, Klein F, Kumar P, Luster AD, Poluektova LY, Rao M, Sanders-Beer BE, Shultz LD, Zack JA. Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary. AIDS Research And Human Retroviruses 2016, 32: 109-119. PMID: 26670361, PMCID: PMC4761823, DOI: 10.1089/aid.2015.0258.Peer-Reviewed Original ResearchConceptsHuman leukocyte antigenHumanized mouse modelHuman immunodeficiency virusMouse modelCell engraftmentHuman hematopoietic cell engraftmentNIH/NIAIDHIV immune responsesImmunodeficient mouse strainsHematopoietic cell engraftmentHuman T cellsHIV reservoirXenogeneic graftImmunodeficiency syndromeHumanized miceImmunodeficiency virusLymphoid structuresLeukocyte antigenNew imaging techniquesT cellsImmune responseImmunodeficient miceHost responseHIV researchInfectious diseases
2015
dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis
Lim S, Kim WJ, Kim YH, Lee S, Koo JH, Lee JA, Yoon H, Kim DH, Park HJ, Kim HM, Lee HG, Yun Kim J, Lee JU, Hun Shin J, Kyun Kim L, Doh J, Kim H, Lee SK, Bothwell AL, Suh M, Choi JM. dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. Nature Communications 2015, 6: 8244. PMID: 26372309, PMCID: PMC4579786, DOI: 10.1038/ncomms9244.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisMultiple sclerosisT cellsAutoimmune encephalomyelitisCytotoxic T-lymphocyte antigen-4T-lymphocyte antigen-4T helper 17 (Th17) cellsCNS inflammatory diseasesTherapeutic mouse modelsEffector T cellsHelper 17 cellsT helper 1Blood-brain barrierCentral nervous systemHuman T cellsHelper 1Antigen-4Inflammatory diseasesMouse modelNervous systemCurrent drugsResident cellsBrain tissueEffective agentCell-permeable peptideCombination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo. The Journal Of Immunology 2015, 194: 950-959. PMID: 25539810, PMCID: PMC4380504, DOI: 10.4049/jimmunol.1401686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, SurfaceAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenCytokinesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunophenotypingIpilimumabLymphocytes, Tumor-InfiltratingNeoplasmsNivolumabProgrammed Cell Death 1 ReceptorSignal TransductionT-Lymphocyte SubsetsConceptsPD-1T cellsCTLA-4Checkpoint blockadeCombination therapyReceptor occupancyCombination immune checkpoint blockadeCTLA-4 immune checkpointsPD-1 receptor occupancyTransitional memory T cellsAnti-PD-1 therapyAnti CTLA-4Immune-based combinationsPD-1 blockadeSoluble IL-2RImmune checkpoint blockadeNK cell functionMemory T cellsTherapy-induced changesT cell activationTumor T cellsHuman T cellsRemarkable antitumor effectImmunologic changesImmunologic effects
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