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 cellsGut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D
Yang X, Huang J, Peng J, Wang P, Wong F, Wang R, Wang D, Wen L. Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D. Frontiers In Immunology 2024, 15: 1413177. PMID: 38903498, PMCID: PMC11187306, DOI: 10.3389/fimmu.2024.1413177.Peer-Reviewed Original ResearchGut microbiotaGerm-free miceToll-like receptor 9Increased gut permeabilityIntestinal microbiotaGut permeabilityT1D developmentGut microbiota compositionFecal samplesTransferred to germ-free miceGut barrier integrityBreg cell differentiationMicrobiota influenceMucin degradationMicrobiota compositionBreg cellsAltered microbiotaMicrobiota impactMicrobiotaGene expressionImmune regulationDevelopment of T1DCell differentiationGutNOD miceTLR5-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
NLRP6 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 diabetesToll-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
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
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 autoantigenTLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model.
Sha S, Pearson JA, Peng J, Hu Y, Huang J, Xing Y, Zhang L, Zhu Y, Zhao H, Wong FS, Chen L, Wen L. TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model. Diabetes 2020, 70: 504-515. PMID: 33154070, PMCID: PMC7881860, DOI: 10.2337/db20-0373.Peer-Reviewed Original ResearchConceptsToll-like receptor 9B cellsNOD miceInterleukin-10IL-10-producing B cellsType 1 diabetes developmentAdaptive immune stimuliΒ-cell autoimmunityB-cell-specific deficiencyNovel therapeutic strategiesInnate immune moleculesB cell-specific deletionT1D developmentDiabetes protectionIL-10TLR9 deficiencyImmune toleranceDiabetes developmentReceptor 9T1D treatmentTLR9 pathwayImmune stimuliMouse modelTherapeutic strategiesMetalloproteinase-1Gut 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
2019
Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions
Pearson JA, Tai N, Ekanayake-Alper DK, Peng J, Hu Y, Hager K, Compton S, Wong FS, Smith PC, Wen L. Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions. Frontiers In Immunology 2019, 10: 2654. PMID: 31798584, PMCID: PMC6863139, DOI: 10.3389/fimmu.2019.02654.Peer-Reviewed Original ResearchConceptsExpansion of TregsNOD miceT cellsMNV4 infectionMucosal immunityNon-obese diabetic (NOD) mouse modelGerm-free NOD miceFirmicutes/Bacteroidetes ratioProinflammatory T cellsRole of norovirusesTuft cell markersDevelopment of T1DInflammatory T cellsCommon enteric virusesB cell subsetsDiabetic mouse modelImmune cell functionType 1 diabetes susceptibilityEnteric virusesNaïve splenocytesT1D protectionTreg numbersImmunological changesMucosal antibodiesT1D development
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 therapiesThe Gut Microbiome in the NOD Mouse
Peng J, Hu Y, Wong FS, Wen L. The Gut Microbiome in the NOD Mouse. Methods In Molecular Biology 2016, 1433: 169-177. PMID: 27032947, DOI: 10.1007/7651_2016_331.Peer-Reviewed Original ResearchConceptsType 1 diabetes developmentNOD miceDiabetes developmentGut bacteriaSusceptible NOD miceNonobese diabetic (NOD) miceBacterial DNA sequencingGut microbiome compositionGut microbiome analysisMouse fecal samplesExcellent mouse modelDiabetic miceMouse modelGut microbiotaGut microbiomeIntestinal contentsMiceCritical modulatorDisease phenotypeFecal samplesMicrobiome compositionStandard protocolMicrobiome analysisHealthPathogenic microorganisms
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 bacteria
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 coxsackievirusesInsulitisIRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice
Tan Q, Majewska-Szczepanik M, Zhang X, Szczepanik M, Zhou Z, Wong FS, Wen L. IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice. Diabetes 2014, 63: 2761-2775. PMID: 24696448, PMCID: PMC4113073, DOI: 10.2337/db13-1504.Peer-Reviewed Original ResearchConceptsDiabetogenic T cellsNOD miceRapid progressionT cellsInterleukin-1 receptor-associated kinase MOrgan-specific autoimmune diseasesType 1 diabetes mellitusAnti-insulin autoantibodiesImmunodeficient NOD miceImpaired glucose toleranceAntigen-presenting functionNonobese diabetic (NOD) miceToll-like receptor pathwayAntigen-presenting cellsEnhanced activationType 1 diabetesInnate immune pathwaysIRAK-M deficiencyInnate immune processesInsulin-secreting pancreatic β-cellsPancreatic β-cellsSevere insulitisAutoimmune diabetesDendritic cellsDiabetes mellitusLong term effect of gut microbiota transfer on diabetes development
Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS, Wen L. Long term effect of gut microbiota transfer on diabetes development. Journal Of Autoimmunity 2014, 53: 85-94. PMID: 24767831, PMCID: PMC4361177, DOI: 10.1016/j.jaut.2014.03.005.Peer-Reviewed Original ResearchConceptsNOD miceGut microbiotaWild-type NOD miceNon-obese diabetic (NOD) miceGut microbiomeMyD88-deficient miceMucosal immune systemOnset of diabetesCD8αβ T cellsType 1 diabetesGut microbiota transferWeeks of ageAutoimmune diabetesT1D developmentDiabetes developmentDiabetic miceMicrobiota transferT cellsLamina propriaLong-term effectsProbiotic treatmentImmune systemLarge intestineDiabetesMice
2013
TLR9 Deficiency Promotes CD73 Expression in T Cells and Diabetes Protection in Nonobese Diabetic Mice
Tai N, Wong FS, Wen L. TLR9 Deficiency Promotes CD73 Expression in T Cells and Diabetes Protection in Nonobese Diabetic Mice. The Journal Of Immunology 2013, 191: 2926-2937. PMID: 23956420, PMCID: PMC3788667, DOI: 10.4049/jimmunol.1300547.Peer-Reviewed Original ResearchConceptsNOD miceCD73 expressionT cellsTLR9 deficiencyDiabetes developmentImmune cellsAnti-inflammatory cytokine productionImproved β-cell functionImportant immune regulatory roleStrong immunosuppressive functionNonobese diabetic (NOD) miceIncidence of diabetesNOD mouse modelPeripheral lymphoid tissuesImmune regulatory roleType 1 diabetesΒ-cell functionNew therapeutic strategiesElevated frequencyNOD backgroundDiabetes protectionDiabetic miceImmunosuppressive functionProinflammatory cytokinesCytokine productionCombination Treatment With Anti-CD20 and Oral Anti-CD3 Prevents and Reverses Autoimmune Diabetes
Hu C, Ding H, Zhang X, Wong FS, Wen L. Combination Treatment With Anti-CD20 and Oral Anti-CD3 Prevents and Reverses Autoimmune Diabetes. Diabetes 2013, 62: 2849-2858. PMID: 23447122, PMCID: PMC3717853, DOI: 10.2337/db12-1175.Peer-Reviewed Original ResearchConceptsT cellsNOD miceB cellsT cell-mediated autoimmune diseaseB cell-directed therapiesB cell depletion therapyCell-mediated autoimmune diseaseDiabetic NOD miceTransgenic NOD miceRegulatory T cellsCD4 T cellsCell-directed therapiesAnti-CD3 treatmentType 1 diabetesCD20 monotherapyImportant preclinical evidenceDepletion therapyT1D developmentDendritic cellsIL-10Preclinical evidenceFurther mechanistic studiesAutoimmune diseasesAnti-CD20Suppressive function