2024
Regulatory 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 cellsTLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model
Pearson J, Hu Y, Peng J, Wong F, Wen L. TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model. Frontiers In Immunology 2024, 15: 1333967. PMID: 38482010, PMCID: PMC10935730, DOI: 10.3389/fimmu.2024.1333967.Peer-Reviewed Original ResearchConceptsToll-like receptor 5Antigen-presenting cellsDendritic cellsType 1 diabetesTLR5-deficientDC developmentCytokine secretionCD4<sup>+</sup> T cell proliferationPathogenesis of type 1 diabetesT cell responsesEnhanced cytokine secretionT cell proliferationWild-type miceSusceptibility to obesitySusceptibility to T1DProinflammatory cytokine secretionGut microbiotaSpontaneous T1DNOD miceAutoimmune diabetesNon-obeseHuman T1DReceptor 5Autoimmune diseasesHyper-secretion
2023
Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice
Chen D, Kakabadse D, Fishman S, Weinstein-Marom H, Davies J, Boldison J, Thayer T, Wen L, Gross G, Wong F. Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice. Frontiers In Immunology 2023, 14: 1227133. PMID: 37731505, PMCID: PMC10507356, DOI: 10.3389/fimmu.2023.1227133.Peer-Reviewed Original ResearchConceptsAntigen-specific CD8Islet-specific T cellsT cellsAutoimmune diabetesB cellsSCID miceMouse modelB lymphocytesNon-obese diabetic (NOD) mouse modelRegulatory B cell functionsProtective cell typesAntigen-specific CD4Pathogenic T cellsT cell cytotoxicityAntigen-presenting cellsCo-transfer experimentsDiabetic mouse modelDiabetic SCID miceType 1 diabetesAntigen-specific cellsB cell functionNovel therapeutic approachesMHC II moleculesSplenic B cellsPD-1Distinct signatures of gut microbiota and metabolites in different types of diabetes: a population-based cross-sectional study
Hu J, Ding J, Li X, Li J, Zheng T, Xie L, Li C, Tang Y, Guo K, Huang J, Liu S, Yan J, Peng W, Hou C, Wen L, Xu A, Zhou Z, Xiao Y. Distinct signatures of gut microbiota and metabolites in different types of diabetes: a population-based cross-sectional study. EClinicalMedicine 2023, 62: 102132. PMID: 37593224, PMCID: PMC10430172, DOI: 10.1016/j.eclinm.2023.102132.Peer-Reviewed Original ResearchAdult-onset T1DHealthy controlsGut microbiotaT1D patientsShort-chain fatty acid-producing bacteriaPopulation-based cross-sectional studyGut microbial alterationsRecent epidemiological dataType 1 diabetesCross-sectional studyT2D patientsIntestinal disturbancesDifferential diagnosisSerum metabolitesEpidemiological dataPatientsStudy subjectsT1DDiabetesSignificant differencesAcid-producing bacteriaMicrobiotaMicrobial profilesNational Key ResearchMicrobial alterationsNLRP6 deficiency expands a novel CD103+ B cell population that confers immune tolerance in NOD mice
Pearson J, Peng J, Huang J, Yu X, Tai N, Hu Y, Sha S, Flavell R, Zhao H, Wong F, Wen L. NLRP6 deficiency expands a novel CD103+ B cell population that confers immune tolerance in NOD mice. Frontiers In Immunology 2023, 14: 1147925. PMID: 36911699, PMCID: PMC9995752, DOI: 10.3389/fimmu.2023.1147925.Peer-Reviewed Original ResearchConceptsNlrp6-deficient miceType 1 diabetesNLRP6 deficiencyB cellsIL-10Non-obese diabetic (NOD) miceType 1 diabetes developmentRole of NLRP6Germ-free miceT cell proliferationB cell populationsIntestinal epithelial cellsBreg populationAutoimmune diabetesNOD miceCrohn's diseaseImmune toleranceDiabetes developmentDiabetic miceImmune cellsCD103Inflammasome proteinsImmune responseNLRP6Gut microbiota
2022
Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity.
Yang ML, Connolly SE, Gee RJ, Lam TT, Kanyo J, Peng J, Guyer P, Syed F, Tse HM, Clarke SG, Clarke CF, James EA, Speake C, Evans-Molina C, Arvan P, Herold KC, Wen L, Mamula MJ. Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity. Diabetes 2022, 71: 1979-1993. PMID: 35730902, PMCID: PMC9450849, DOI: 10.2337/db21-0989.Peer-Reviewed Original ResearchConceptsType 1 diabetesNOD miceMurine type 1 diabetesHuman type 1 diabetesDecreased glucose-stimulated insulin secretionAnti-insulin autoimmunityPrediabetic NOD miceGlucose-stimulated insulin secretionOnset Type 1T cell responsesOnset of hyperglycemiaCirculation of patientsAutoreactive CD4Insulin ratioInsulin secretionDiabetesPancreatic isletsType 1Islet proteinsOxidative stressAutoimmunitySelect groupMiceCarbonyl modificationOnset
2021
IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice
Huang J, Tan Q, Tai N, Pearson JA, Li Y, Chao C, Zhang L, Peng J, Xing Y, Zhang L, Hu Y, Zhou Z, Wong FS, Wen L. IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice. Frontiers In Immunology 2021, 12: 702955. PMID: 34394099, PMCID: PMC8362616, DOI: 10.3389/fimmu.2021.702955.Peer-Reviewed Original ResearchConceptsNOD miceProportion of neutrophilsT cellsGut microbiotaDiabetes developmentT cell-mediated destructionT cell receptor transgenicType 1 diabetes developmentAccelerated diabetes developmentInhibition of diabetesModulation of InnatePathogenicity of CD4Cell-mediated destructionAdaptive immune cellsObese diabetic miceT regulatory (Treg) cellsDevelopment of diabetesPrevention of diabetesActivation of CD4Modulation of neutrophilsType 1 diabetesGut microbiota compositionInsulin-producing β-cellsSevere insulitisSpontaneous diabetesInnate immunity in latent autoimmune diabetes in adults
Huang J, Pearson JA, Wong FS, Wen L, Zhou Z. Innate immunity in latent autoimmune diabetes in adults. Diabetes/Metabolism Research And Reviews 2021, 38: e3480. PMID: 34156143, PMCID: PMC8813511, DOI: 10.1002/dmrr.3480.Peer-Reviewed Original ResearchConceptsType 1 diabetesDendritic cellsImmune cellsT cellsInnate immunityPathogenesis of LADALatent autoimmune diabetesAdaptive immune cellsPancreas of patientsType 2 diabetesImmune-associated genesIslet β-cellsAutoimmune diabetesClinical featuresImmunological reasonsAutoimmune diseasesRat modelB cellsDiabetesΒ-cellsImmunityPotential rolePathogenesisLADADiseaseInflammasomes and Type 1 Diabetes
Pearson JA, Wong FS, Wen L. Inflammasomes and Type 1 Diabetes. Frontiers In Immunology 2021, 12: 686956. PMID: 34177937, PMCID: PMC8219953, DOI: 10.3389/fimmu.2021.686956.Peer-Reviewed Original ResearchConceptsType 1 diabetesMultiprotein complexesEnhanced toleranceMicrobial ligandsIslet autoantibody developmentImmune responseGenetic associationMicrobial stimulationAvailable inhibitorsImportant modulatorType 1 diabetes susceptibilityPathwayDiabetes susceptibilityAutoimmune processMicrobiota compositionAutoantibody developmentMicrobiotaAnimal modelsInflammasomeActivationGenetic riskType 1DiabetesHumansRoleToll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function
Huang J, Peng J, Pearson JA, Efthimiou G, Hu Y, Tai N, Xing Y, Zhang L, Gu J, Jiang J, Zhao H, Zhou Z, Wong FS, Wen L. Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function. Cellular & Molecular Immunology 2021, 18: 328-338. PMID: 33432061, PMCID: PMC8027372, DOI: 10.1038/s41423-020-00590-8.Peer-Reviewed Original ResearchConceptsType 1 diabetes developmentToll-like receptorsType 1 diabetesDiabetes developmentB cellsTLR7 deficiencyNOD miceB cell differentiationT cellsClassical MHC class I moleculesHuman type 1 diabetesImmunodeficient NOD miceNOD B cellsDiabetogenic T cellsAntigen-presenting functionNonobese diabetic (NOD) miceT cell responsesB cell functionMHC class I moleculesPattern recognition receptorsT cell activationPathogen molecular patternsClass I moleculesDiabetogenic CD4Cytotoxic CD8
2020
Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes.
Thayer TC, Davies J, Pearson JA, Hanna SJ, Wen L, Wong FS. Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes. Diabetes 2020, 70: 529-537. PMID: 33122391, PMCID: PMC8176215, DOI: 10.2337/db19-1050.Peer-Reviewed Original ResearchConceptsType 1 diabetesCD3/CD28T cellsAutoreactive cellsMHC-independent mechanismsNOD mouse modelT cell cytotoxicityΒ-cell destructionStromal cell regulationT cell receptor engagementPeripheral toleranceDiabetes developmentEffector functionsMouse modelAntigen sensitivityCD8Suppressive mechanismsStromal cellsType 1MHCReceptor engagementLNSCDiabetesIndependent mechanismsCD28Insulin-Reactive T Cells Convert Diabetogenic Insulin-Reactive VH125 B Cells Into Tolerogenic Cells by Reducing Germinal Center T:B Cell Interactions in NOD Mice
Pearson JA, Li Y, Majewska-Szczepanik M, Guo J, Zhang L, Liu Y, Wong FS, Wen L. Insulin-Reactive T Cells Convert Diabetogenic Insulin-Reactive VH125 B Cells Into Tolerogenic Cells by Reducing Germinal Center T:B Cell Interactions in NOD Mice. Frontiers In Immunology 2020, 11: 585886. PMID: 33262765, PMCID: PMC7688534, DOI: 10.3389/fimmu.2020.585886.Peer-Reviewed Original ResearchConceptsB cell interactionsTransgenic NOD miceNOD miceT cellsB cellsT1D developmentAntigen-specific regulatory T cellsInsulin-reactive B cellsInsulin-reactive T cellsNon-obese diabetic (NOD) miceGerminal center TInsulin-reactive CD4Non-germinal centerCell interactionsCostimulatory molecule expressionRegulatory T cellsType 1 diabetesGC B cellsTolerogenic cellsAdoptive transferDiabetic miceTGFβ secretionMolecule expressionIgG isotypeKey autoantigenAltered Systemic and Intestinal IgA Immune Responses in Individuals With Type 1 Diabetes
Huang J, Huang G, Li X, Hu F, Xie Z, Xiao Y, Luo S, Chao C, Guo K, Wong FS, Zhou Z, Wen L. Altered Systemic and Intestinal IgA Immune Responses in Individuals With Type 1 Diabetes. The Journal Of Clinical Endocrinology & Metabolism 2020, 105: dgaa590. PMID: 32860693, PMCID: PMC7549925, DOI: 10.1210/clinem/dgaa590.Peer-Reviewed Original ResearchConceptsIgA-bound bacteriaType 1 diabetesHealthy control individualsIgA immune responseControl individualsIgA immunityAutoantibody titersIgA concentrationsImmune responseType 1 diabetes patientsΒ-cell autoimmunityLonger disease durationSerum IgA concentrationNovel therapeutic targetEnzyme-linked immunosorbentDisease durationIgA levelsDiabetes patientsDiabetes displayGut homeostasisBlood samplesOral cavityTherapeutic targetDiabetesHost immunityGut microbial metabolites alter IgA immunity in type 1 diabetes
Huang J, Pearson JA, Peng J, Hu Y, Sha S, Xing Y, Huang G, Li X, Hu F, Xie Z, Xiao Y, Luo S, Chao C, Wong F, Zhou Z, Wen L. Gut microbial metabolites alter IgA immunity in type 1 diabetes. JCI Insight 2020, 5 PMID: 32298241, PMCID: PMC7259536, DOI: 10.1172/jci.insight.135718.Peer-Reviewed Original ResearchConceptsType 1 diabetesGut microbiotaNOD miceImmune responseGerm-free NOD miceIgA immune responseIgA-mediated immunityHealthy control subjectsPotential therapeutic agentShort-chain fatty acid productionIgA immunityT1D preventionIgA responsesControl subjectsDecreased severityT1DTherapeutic agentsFunctional effectsMicrobiotaDiabetesPatientsUnderlying mechanismMiceImmunitySCFAMouse Models of Autoimmune Diabetes: The Nonobese Diabetic (NOD) Mouse
Chen D, Thayer TC, Wen L, Wong FS. Mouse Models of Autoimmune Diabetes: The Nonobese Diabetic (NOD) Mouse. Methods In Molecular Biology 2020, 2128: 87-92. PMID: 32180187, PMCID: PMC8253669, DOI: 10.1007/978-1-0716-0385-7_6.Peer-Reviewed Original ResearchConceptsNonobese diabetic (NOD) miceType 1 diabetesDiabetic miceMouse modelHuman type 1 diabetesUnmanipulated NOD miceAutoimmune thyroid diseaseDifferent mouse modelsAutoimmune diathesesAutoimmune diabetesNOD miceSpontaneous diabetesAutoimmune typeThyroid diseaseRodent modelsDiabetesIncidence of diseaseNatural historyGenetic susceptibilityMiceNumerous transgenicKnockout modelsDiseaseAutoimmuneSialadenitis
2016
Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice
Hu Y, Jin P, Peng J, Zhang X, Wong FS, Wen L. Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice. Journal Of Autoimmunity 2016, 72: 47-56. PMID: 27178773, PMCID: PMC4958594, DOI: 10.1016/j.jaut.2016.05.001.Peer-Reviewed Original ResearchConceptsAntigen-presenting cellsType 1 diabetesAutoimmune diabetes developmentDiabetes developmentPregnant mothersEarly-life antibiotic exposureTolerogenic antigen-presenting cellsUntreated control miceInflammatory T cellsDifferent immunological responsesGut microbiota compositionDifferent immune responsesImportant environmental agentsGut bacterial compositionEarly time pointsNOD miceControl miceAutoimmune diseasesPrenatal exposureLymphoid organsAntibiotic exposureT cellsImmune responseImmunological responseNew therapies
2015
Maternal Antibiotic Treatment Protects Offspring from Diabetes Development in Nonobese Diabetic Mice by Generation of Tolerogenic APCs
Hu Y, Peng J, Tai N, Hu C, Zhang X, Wong FS, Wen L. Maternal Antibiotic Treatment Protects Offspring from Diabetes Development in Nonobese Diabetic Mice by Generation of Tolerogenic APCs. The Journal Of Immunology 2015, 195: 4176-4184. PMID: 26401004, PMCID: PMC4765177, DOI: 10.4049/jimmunol.1500884.Peer-Reviewed Original ResearchConceptsNOD miceTolerogenic APCsDiabetes developmentT cell-mediated autoimmune diseaseDiabetogenic CD8 T cellsCell-mediated autoimmune diseasePolymyxin BCD8 T cellsNonobese diabetic (NOD) miceType 1 diabetesHost immune systemIslet β-cellsAutoimmune diabetesDifferent time pointsImmune toleranceDiabetic miceAutoimmune diseasesProfound protectionT cellsImmune responseProtective effectCommensal microbiotaGut microbiotaSusceptible individualsCommensal bacteriaNLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets
Hu C, Ding H, Li Y, Pearson JA, Zhang X, Flavell RA, Wong FS, Wen L. NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 11318-11323. PMID: 26305961, PMCID: PMC4568693, DOI: 10.1073/pnas.1513509112.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsCarrier ProteinsCell MovementChemokine CCL5Chemokine CXCL10ChemotaxisDiabetes Mellitus, Type 1Gene ExpressionHumansInflammasomesInterferon Regulatory Factor-1Interleukin-1betaIslets of LangerhansMice, Inbred C57BLMice, Inbred NODMice, KnockoutMice, SCIDNLR Family, Pyrin Domain-Containing 3 ProteinReceptors, CCR5Receptors, CXCR3Reverse Transcriptase Polymerase Chain ReactionSignal TransductionTime FactorsT-LymphocytesConceptsType 1 diabetesLeucine-rich repeatsNonobese diabetic (NOD) mouse modelPancreatic isletsRegulation of chemotaxisTreatment of T1D.Role of TLRsDevelopment of T1DChemokine receptor CCR5Diabetic mouse modelT cell migrationT cell activationPresence of NLRP3Pancreatic islet cellsNLRP3 ablationOligomerization domainNLRP3 inflammasomeReceptor CCR5T cellsTh1 differentiationInflammasome pathwayAdaptive immunityMouse modelAnimal modelsIslet cellsThe role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity
Tai N, Wong FS, Wen L. The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Reviews In Endocrine And Metabolic Disorders 2015, 16: 55-65. PMID: 25619480, PMCID: PMC4348024, DOI: 10.1007/s11154-015-9309-0.Peer-Reviewed Original ResearchConceptsGut microbiotaAutoimmune type 1 diabetesType 2 diabetes mellitusInsulin-resistant type 2 diabetesMajor public health concernAltered gut microbiotaDevelopment of T1DType 2 diabetesType 1 diabetesGut microbiota compositionPublic health concernDiabetes mellitusPersistent hyperglycemiaMetabolic disordersRodent modelsMicrobiota compositionType 1ObesityDiabetesHealth concernPotential mechanismsMicrobiotaT2DT1DDisease development
2014
Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice
McCall K, Thuma J, Courreges M, Benencia F, James C, Malgor R, Kantake N, Mudd W, Denlinger N, Nolan B, Wen L, Schwartz F. Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice. Endocrinology 2014, 156: 453-461. PMID: 25422874, PMCID: PMC4298321, DOI: 10.1210/en.2013-2006.Peer-Reviewed Original ResearchConceptsToll-like receptor 3TLR3 knockout miceWild-type miceNOD miceKnockout miceRole of TLR3Receptor 3Type 1 diabetes mellitusFemale NOD miceProne NOD miceNonobese diabetic (NOD) miceIncidence of diabetesType 1 diabetesViral double-stranded RNAGroup B coxsackievirusesHuman T1DMDiabetes mellitusDiabetic miceMouse modelT1DMTLR3 knockoutUninfected counterpartsUninfected animalsB coxsackievirusesInsulitis