2025
Latent EBV enhances the efficacy of anti-CD3 mAb in Type 1 diabetes
Lledó-Delgado A, Preston-Hurlburt P, Higdon L, Hu A, James E, Lim N, Long S, McNamara J, Nguyen H, Serti E, Sumida T, Herold K. Latent EBV enhances the efficacy of anti-CD3 mAb in Type 1 diabetes. Nature Communications 2025, 16: 5033. PMID: 40447640, PMCID: PMC12125364, DOI: 10.1038/s41467-025-60276-5.Peer-Reviewed Original ResearchConceptsCD8+ T cellsEBV-seropositive individualsType 1 diabetesT cellsImmune cellsAntigen-specific CD8+ T cellsDiagnosis of type 1 diabetesEBV-seronegative patientsEBV-seropositive patientsT cell activation pathwaysRegulatory T cellsAnti-CD3 mAbInnate immune cellsPeripheral blood cellsT cell receptorProgression of diseaseContext of type 1 diabetesImpaired signaling pathwaysTeplizumabClinical trialsLatent EBVBlood cellsSingle cell transcriptomicsModulate progressionMTOR signalingMHC Class II Sharing Appears to Promote Intestinal Allograft Tolerance Through Linked Suppression in a Large Animal Model.
Gunes M, Patwardhan S, Merl S, Yang K, Jones R, Chen B, Manell E, Hong J, Jordache P, Atta H, Chauhan I, Almesallmy A, Shamim A, Agwuncha O, Mulder H, Dasari A, Hajosi D, Hawley R, Nowak G, Pereira M, Ko H, Ekanayake-Alper D, Martinez M, Sachs D, Kato T, Yamada K, Sykes M, Weiner J. MHC Class II Sharing Appears to Promote Intestinal Allograft Tolerance Through Linked Suppression in a Large Animal Model. Transplantation 2025 PMID: 40392586, DOI: 10.1097/tp.0000000000005420.Peer-Reviewed Original ResearchMajor histocompatibility complexAntigen-presenting cells in vivoDonor regulatory T cellsInduction of transplantation toleranceMixed lymphocyte reaction assayClass II matchingTreg-mediated toleranceDonor-specific hyporesponsivenessRegulatory T cellsClinically relevant modelEvidence of toleranceClass II allelesCells in vivoAllograft toleranceTransplantation toleranceGraft toleranceT cellsIntestinal transplantationAntigen-SpecificII allelesIn vitro analysisAnimal modelsClinical protocolsHistocompatibility complexReaction assayTolerance requires diversity (of antigen presenting cells).
Jacobsen D, Eisenbarth S. Tolerance requires diversity (of antigen presenting cells). Science Immunology 2025, 10: eady4136. PMID: 40315295, DOI: 10.1126/sciimmunol.ady4136.Peer-Reviewed Original ResearchHuman Type 1 Conventional Dendritic Cells Contribute to Skin Transplant Rejection
Borges T, Lee C, Mucciarone K, Lima K, Lape I, Lima-Filho M, Ayoama B, Kollar B, Gassen R, Bonorino C, Talbot S, Pomahac B, Lian C, Murphy G, Riella L. Human Type 1 Conventional Dendritic Cells Contribute to Skin Transplant Rejection. American Journal Of Transplantation 2025 PMID: 40286910, DOI: 10.1016/j.ajt.2025.04.016.Peer-Reviewed Original ResearchType 1 conventional dendritic cellsHuman skin allograftsDendritic cellsSkin allograftsT cellsDecreased HLA-DR expressionIncreased regulatory T cellsMurine skin transplantationSkin transplant rejectionHLA-DR expressionRegulatory T cellsAllogeneic T cellsHuman skin graftsHumanized transplantation modelUpper extremity transplant recipientsInduce immune modulationImmunogenic tissueTransplant recipientsTransplantation modelTransplant rejectionCDC1 subsetImmune modulationCDC1sSkin transplantationSkin graftsSafety and Antitumor Activity of a Novel aCD25 Treg Depleter RG6292 as a Single Agent and in Combination with Atezolizumab in Patients with Solid Tumors
Gambardella V, Ong M, Rodriguez-Ruiz M, Machiels J, Sanmamed M, Galvao V, Spreafico A, Renouf D, Luen S, Galot R, de Spéville B, Calvo E, Naing A, Curdt S, Kolben T, Rossmann E, Tanos T, Smart K, Amann M, Xie Y, Xu L, Alcaide E, Städler N, Justies N, Boetsch C, Karanikas V, Schnetzler G, Rohrberg K. Safety and Antitumor Activity of a Novel aCD25 Treg Depleter RG6292 as a Single Agent and in Combination with Atezolizumab in Patients with Solid Tumors. Cancer Research Communications 2025, 5: 422-432. PMID: 39983024, PMCID: PMC11891644, DOI: 10.1158/2767-9764.crc-24-0638.Peer-Reviewed Original ResearchConceptsRecommended phase II dosePhase II doseMaximum tolerated dosePhase I studyTreg depletionSolid tumorsII doseTolerated doseResistance to cancer immunotherapyRegulatory T-cell depletionImmunosuppressive regulatory T cellsEffector T cell functionAdvanced solid tumorsT-cell depletionRegulatory T cellsAnti-CD25 antibodyFrequent adverse eventsT cell functionDose-dependent depletionIL-2 signalingAtezolizumab combinationDeplete TregsTreg reductionDose escalationPeripheral TregsAssociation between PD-1 expression on tumor-infiltrating regulatory T cells and resistance to first-line nivolumab in advanced clear cell renal cell carcinoma: Insights from the HCRN GU16-260 clinical trial.
Mohanna R, Simsek B, El Ahmar N, Jegede O, Matar S, Paul M, Nabil Laimon Y, Roberti De Oliveira G, Delcea A, Choueiri T, Braun D, Haas N, Hammers H, Bilen M, Stein M, Sosman J, Wu C, McDermott D, Atkins M, Signoretti S. Association between PD-1 expression on tumor-infiltrating regulatory T cells and resistance to first-line nivolumab in advanced clear cell renal cell carcinoma: Insights from the HCRN GU16-260 clinical trial. Journal Of Clinical Oncology 2025, 43: 590-590. DOI: 10.1200/jco.2025.43.5_suppl.590.Peer-Reviewed Original ResearchAdvanced clear cell renal cell carcinomaClear cell renal cell carcinomaProgression-free survivalPD-1 expressionTumor-infiltrating TregsCell renal cell carcinomaRegulatory T cellsPD-1Renal cell carcinomaClinical trialsCell carcinomaT cellsEfficacy of PD-1 blockadeInhibition of PD-1 signalingLevel of PD-1 expressionShorter median progression-free survivalTumor-infiltrating regulatory T cellsAssociated with progression-free survivalMedian progression-free survivalPercentage of PD-1First-line nivolumabFirst-line settingPD-1 blockadePD-1 signalingLog-rank test
2024
Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma
Lu B, Lucca L, Lewis W, Wang J, Nogueira C, Heer S, Rayon-Estrada V, Axisa P, Reeves S, Buitrago-Pocasangre N, Pham G, Kojima M, Wei W, Aizenbud L, Bacchiocchi A, Zhang L, Walewski J, Chiang V, Olino K, Clune J, Halaban R, Kluger Y, Coyle A, Kisielow J, Obermair F, Kluger H, Hafler D. Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma. Nature Immunology 2024, 26: 82-91. PMID: 39609626, DOI: 10.1038/s41590-024-02023-4.Peer-Reviewed Original ResearchCD8+ T cellsAnti-tumor immunityRegulatory T cellsT cellsSubpopulation of CD8+ T cellsCytotoxic CD8+ T cellsHuman CD8+ T cellsTumor antigen-specific CD8Impaired anti-tumor immunityTumor antigen-specificPoor overall survivalTumor rejectionKIR expressionOverall survivalTumor antigensImmune evasionCellular mediatorsHuman cancersCD8MelanomaTumorTranscriptional programsFunctional heterogeneityImmunityPatientsTMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models
Jiang Z, Wang H, Wang X, Duo H, Tao Y, Li J, Li X, Liu J, Ni J, Wu E, Xiang H, Guan C, Wang X, Zhang K, Zhang P, Hou Z, Liu Y, Wang Z, Su B, Li B, Hao Y, Li B, Wu X. TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models. Journal Of Clinical Investigation 2024, 135: e179874. PMID: 39480507, PMCID: PMC11684806, DOI: 10.1172/jci179874.Peer-Reviewed Original ResearchEndoplasmic reticulum stressER-associated degradationSuppressive functionTreg cellsFoxp3 stabilityReactive oxygen speciesSuppressive function of Treg cellsFunction of Treg cellsExacerbated inflammatory phenotypeAnti-tumor immunityTreg suppressive functionRegulatory T cellsTreg cell stabilityT cell hyperactivationAutoimmune mouse modelReactive oxygen species homeostasisTreg signatureT cellsTregsInflammatory phenotypeReactive oxygen species scavengingMouse modelTMED4Excessive reactive oxygen speciesProtein 4First-in-human phase 1 dose-escalation results with livmoniplimab, an antibody targeting the GARP:TGF-ß1 complex, as monotherapy and in combination with the anti–PD-1 antibody budigalimab in patients with advanced solid tumors
Shimizu T, Powderly J, Razak A, LoRusso P, Miller K, Kao S, Kongpachith S, Tribouley C, Graham M, Stoll B, Patel M, Sahtout M, Blaney M, Leibman R, Golan T, Tolcher A. First-in-human phase 1 dose-escalation results with livmoniplimab, an antibody targeting the GARP:TGF-ß1 complex, as monotherapy and in combination with the anti–PD-1 antibody budigalimab in patients with advanced solid tumors. Frontiers In Oncology 2024, 14: 1376551. PMID: 39534099, PMCID: PMC11555770, DOI: 10.3389/fonc.2024.1376551.Peer-Reviewed Original ResearchAdvanced solid tumorsDose-escalation phaseDose escalationSolid tumorsSurface of regulatory T cellsRecommended phase 2 doseSuppress antitumor immune responsesCombination therapy cohortsDose-proportional PKMonotherapy-treated patientsPhase 2 doseMedian response durationAntitumor immune responseDose-limiting toxicityTherapy-treated patientsRegulatory T cellsMaximum administered doseFirst-in-humanDose escalation resultsGlycoprotein A repetitionsPromote tumor growthBlood biomarker dataDose expansionPretreated patientsEscalating dosesFoxp3+ regulatory T cells reside within the corneal epithelium and co-localize with limbal stem cells
Tahvildari M, Me R, Setia M, Gao N, Suvas P, McClellan S, Suvas S. Foxp3+ regulatory T cells reside within the corneal epithelium and co-localize with limbal stem cells. Experimental Eye Research 2024, 249: 110123. PMID: 39396695, PMCID: PMC11622170, DOI: 10.1016/j.exer.2024.110123.Peer-Reviewed Original ResearchConceptsLimbal stem cellsRegulatory T cellsResident TregsT cellsFoxp3<sup>+</sup> regulatory T cellsLimbal stem cell functionMouse modelCorneal epithelial wound healingModel of mechanical injuryStem cellsDepletion of TregsCell functionEpithelial wound healingEpithelial cell functionWound healingStem cell functionMechanical injuryAnti-CD25Epithelial healingSubconjunctival injectionCorneal epitheliumCorneal stromaTregsCornealCorneaRegulatory CD4+ T cells redirected against pathogenic CD8+ T cells protect NOD mice from development of autoimmune diabetes
Kakabadse D, Chen D, Fishman S, Weinstein-Marom H, Davies J, Wen L, Gross G, Wong F. Regulatory CD4+ T cells redirected against pathogenic CD8+ T cells protect NOD mice from development of autoimmune diabetes. Frontiers In Immunology 2024, 15: 1463971. PMID: 39351219, PMCID: PMC11439686, DOI: 10.3389/fimmu.2024.1463971.Peer-Reviewed Original ResearchCD8+ T cellsCD4+ T cellsAntigen-specific CD8+ T cellsDevelopment of autoimmune diabetesRegulatory T cellsCo-transfer experimentsT cellsNOD miceAutoimmune diabetesAntigen-specific CD4+ T cellsRegulatory CD4+ T cellsAntigen-specific cytotoxic CD8Pathogenic CD8+ T cellsPre-diabetic NOD micePolyclonal CD4+ T cellsDevelopment of type 1 diabetesSuppresses autoimmune diabetesAntigen-specific CD4Expression of Foxp3Young NOD miceT cell-T cellMarkers in vitroType 1 diabetesAdoptive transferTreg cellsAn autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction
Sumida T, Lincoln M, He L, Park Y, Ota M, Oguchi A, Son R, Yi A, Stillwell H, Leissa G, Fujio K, Murakawa Y, Kulminski A, Epstein C, Bernstein B, Kellis M, Hafler D. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction. Science Translational Medicine 2024, 16: eadp1720. PMID: 39196959, PMCID: PMC12051482, DOI: 10.1126/scitranslmed.adp1720.Peer-Reviewed Original ResearchConceptsForkhead box P3Autoimmune diseasesCD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cellsMultiple sclerosisFoxp3<sup>+</sup> regulatory T cellsRegulatory T cell dysfunctionPR domain zinc finger protein 1Zinc finger protein 1Glucocorticoid-regulated kinase 1Regulatory T cellsT cell dysfunctionDisorder of young adultsAutoimmune disease multiple sclerosisDisease multiple sclerosisExpression of serumTranscriptional circuitsEpigenomic profilingShort isoformPrevent autoimmunityUpstream regulatorT cellsHuman autoimmunityEvolutionary emergenceKinase 1Molecular mechanismsSpatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis-associated thymoma
Yasumizu Y, Kinoshita M, Zhang M, Motooka D, Suzuki K, Nojima S, Koizumi N, Okuzaki D, Funaki S, Shintani Y, Ohkura N, Morii E, Okuno T, Mochizuki H. Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis-associated thymoma. Cell Reports 2024, 43: 114677. PMID: 39180749, DOI: 10.1016/j.celrep.2024.114677.Peer-Reviewed Original ResearchMyasthenia gravisMedullary thymic epithelial cellsGerminal center responseRegulatory T cellsImmune cell compositionMigratory dendritic cellsThymic epithelial cellsCortico-medullary junctionImmune microenvironmentDendritic cellsT cellsChemokine patternsThymus abnormalitiesHyperplasia samplesThymomaSpatial transcriptomic analysisEpithelial cellsMG pathologyMedullary regionCenter responseMedullaCell compositionCortical regionsPathologyCellsSingle-Cell Profiling Reveals Immune Aberrations in Progressive Idiopathic Pulmonary Fibrosis.
Unterman A, Zhao A, Neumark N, Schupp J, Ahangari F, Cosme C, Sharma P, Flint J, Stein Y, Ryu C, Ishikawa G, Sumida T, Gomez J, Herazo-Maya J, Dela Cruz C, Herzog E, Kaminski N. Single-Cell Profiling Reveals Immune Aberrations in Progressive Idiopathic Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2024, 210: 484-496. PMID: 38717443, PMCID: PMC11351796, DOI: 10.1164/rccm.202306-0979oc.Peer-Reviewed Original ResearchStable idiopathic pulmonary fibrosisIdiopathic pulmonary fibrosisPeripheral blood mononuclear cellsProgressive idiopathic pulmonary fibrosisPeripheral immune systemT cellsPulmonary fibrosisCohort of IPF patientsAssociated with decreased survivalIdiopathic pulmonary fibrosis patientsPeripheral blood mononuclear cell samplesPeripheral blood cell populationsImmune systemFraction of TregsRegulatory T cellsBlood mononuclear cellsBlood cell populationsFlow cytometry analysisImmune aberrationsIPF patientsTregsMononuclear cellsSingle-cell RNA sequencingLung homogenatesMonocyte chemoattractantDistinct Localization, Transcriptional Profiles, and Functionality in Early Life Tonsil Regulatory T Cells.
Verma S, Bradley M, Gray J, Dogra P, Caron D, Maurrasse S, Grunstein E, Waldman E, Jang M, Pethe K, Farber D, Connors T. Distinct Localization, Transcriptional Profiles, and Functionality in Early Life Tonsil Regulatory T Cells. The Journal Of Immunology 2024, 213: 306-316. PMID: 38905110, PMCID: PMC11304551, DOI: 10.4049/jimmunol.2300890.Peer-Reviewed Original ResearchRegulatory T cellsT cellsTreg biologyCD4+ regulatory T cellsCD8+ T cellsIncreased Foxp3 expressionProportion of TregsProduction of IL-10Paired blood samplesHigher proliferative capacityTranscriptional profilesAdult TregsTreg activityFoxp3 expressionTreg identityExtrafollicular regionsTregsIL-10Primary siteProtective immunityProliferative capacityImmune responseImmunological developmentAdult subjectsImmune systemA phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes
Bender C, Wiedeman A, Hu A, Ylescupidez A, Sietsema W, Herold K, Griffin K, Gitelman S, Long S, Gottlieb P, Strock R, Chesshir L, Redondo M, Williams C, Clements M, Moore W, DiMeglio L, Legge M, Mullen M, Sanchez J, Spall M, Woerner S, Gaglia J, Resnick B, Bryant N, Krishfield S, Turley J, Koshy N, Mackey M, Guttmann-Bauman I, Fitch R, Bartholow L, Shelso J, Al Nofal A, Hanisch K, Casas L, Thurlow B, Gottschalk M, Hashiguchi M, Paglia L, Lam A, Sanda S, Torok C, Wesch R, Moore D, Russell W, Smith T, Brown A, Brendle F, Haller M, Cintron M, Baidal D, Matheson D, Blaschke C, Moran A, Pappensus E, Leschyshyn J, Street A. A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes. Science Translational Medicine 2024, 16: eadn2404. PMID: 38718135, DOI: 10.1126/scitranslmed.adn2404.Peer-Reviewed Original ResearchConceptsRegulatory T cellsType 1 diabetesT cellsC-peptideFoxp3<sup>+</sup> regulatory T cellsNew-onset type 1 diabetesResidual B-cell functionPhase 1 clinical trialAutoimmune type 1 diabetesC-peptide preservationHigh-dose cohortPhase 2 randomized trialYears compared to placeboNew-onset T1DBaseline C-peptidePeripheral blood samplesSuppression in vitroDetected 1 weekMatching placeboAdoptive transferDouble-blindHigh-dosePrevent autoimmunityLow-doseFold expansionNew insights into macrophage polarization and its prognostic role in patients with colorectal cancer liver metastasis
Khanduri I, Maki H, Verma A, Katkhuda R, Anandappa G, Pandurengan R, Zhang S, Mejia A, Tong Z, Solis Soto L, Jadhav A, Wistuba I, Menter D, Kopetz S, Parra E, Vauthey J, Maru D. New insights into macrophage polarization and its prognostic role in patients with colorectal cancer liver metastasis. BJC Reports 2024, 2: 37. PMID: 39516662, PMCID: PMC11523988, DOI: 10.1038/s44276-024-00056-8.Peer-Reviewed Original ResearchColorectal cancer liver metastasesRecurrence-free survivalCancer liver metastasesTumor-associated macrophagesT cell subtypesPreoperative chemotherapyLiver metastasesT cellsColorectal cancer liver metastases patientsM2 macrophagesAssociated with shorter recurrence-free survivalShorter recurrence-free survivalPredictor of favorable prognosisRegulatory T cellsMacrophage polarizationCytotoxic T cellsHelper T cellsDensity of M2 macrophagesCause of mortalityFavorable prognosisPrognostic roleM2 macrophage polarizationTumor biologyTumor samplesColorectal cancerImmune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions
Knoedler L, Dean J, Diatta F, Thompson N, Knoedler S, Rhys R, Sherwani K, Ettl T, Mayer S, Falkner F, Kilian K, Panayi A, Iske J, Safi A, Tullius S, Haykal S, Pomahac B, Kauke-Navarro M. Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions. Frontiers In Immunology 2024, 15: 1372862. PMID: 38650942, PMCID: PMC11033354, DOI: 10.3389/fimmu.2024.1372862.Peer-Reviewed Original ResearchConceptsRegulatory myeloid cellsSolid organ transplantationVascularized Composite AllotransplantationMesenchymal stromal cellsT cellsTransplant patientsCellular therapyChimeric antigen receptor T cellsTransplant surgerySide effectsIncreased risk of malignancyProgression to chronic rejectionAcute rejection ratesPerioperative treatment strategiesRegulatory T cellsPromote immune toleranceRisk of malignancySystemic side effectsRelated side effectsCell typesImprove transplant survivalCAR-TCell therapy applicationsImmunosuppressive regimensChronic rejectionHuman lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy
Chen J, Nieman L, Spurrell M, Jorgji V, Elmelech L, Richieri P, Xu K, Madhu R, Parikh M, Zamora I, Mehta A, Nabel C, Freeman S, Pirl J, Lu C, Meador C, Barth J, Sakhi M, Tang A, Sarkizova S, Price C, Fernandez N, Emanuel G, He J, Van Raay K, Reeves J, Yizhak K, Hofree M, Shih A, Sade-Feldman M, Boland G, Pelka K, Aryee M, Mino-Kenudson M, Gainor J, Korsunsky I, Hacohen N. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nature Immunology 2024, 25: 644-658. PMID: 38503922, PMCID: PMC12096941, DOI: 10.1038/s41590-024-01792-2.Peer-Reviewed Original ResearchT cellsDendritic cellsImmune hubAssociated with response to immunotherapyMature tertiary lymphoid structuresOrganization of immune cellsIntratumoral immune responsePD-1 blockadeRegulatory dendritic cellsResponse to immunotherapyAbundant T cellsRegulatory T cellsTertiary lymphoid structuresLung cancer specimensHuman lung cancerImmunogenic tumorsImmunotherapy outcomesPD-1Lymphoid structuresCancer specimensImmune cellsLung cancerHuman tumorsImmune responseTumorThe regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases
Sumida T, Cheru N, Hafler D. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nature Reviews Immunology 2024, 24: 503-517. PMID: 38374298, PMCID: PMC11216899, DOI: 10.1038/s41577-024-00994-x.Peer-Reviewed Original ResearchTreg cell dysfunctionTreg cellsAutoimmune diseasesCell dysfunctionSuppressive function of Treg cellsDifferentiation of regulatory T cellsFunction of Treg cellsDiscovery of Foxp3Foxp3-independent mechanismsTreg cell suppressionRegulatory T cellsTreg cell functionTranscription factor Foxp3Systemic lupus erythematosusRegulate immune responsesInflammatory bowel diseaseFOXP3 mutationsFoxp3-dependentSystemic autoinflammationRegulatory TIPEX syndromeCell lineage determinationT cellsTregsLupus erythematosus
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