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 cellsTlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis
Wang P, Yang X, Zhang L, Sha S, Huang J, Peng J, Gu J, Pearson J, Hu Y, Zhao H, Wong F, Wang Q, Wen L. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis. Nature Communications 2024, 15: 4232. PMID: 38762479, PMCID: PMC11102548, DOI: 10.1038/s41467-024-48611-8.Peer-Reviewed Original ResearchConceptsToll-like receptor 9Gut microbiotaGut microbial communityTransferred to germ-free miceB cellsGerm-free miceTLR9 deficiencyKO miceGene sequencesGerminal center B cellsMicrobial communitiesMarginal zone B cellsGut dysbiosisFollicular helper cellsSelf-DNAMetabolic homeostasisAssociated with increased frequencyPro-inflammatory stateFat tissue inflammationGutHigh-fat dietMicrobiotaHelper cellsT cellsControl mice
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-1
2022
Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation
Ding P, Tan Q, Wei Z, Chen Q, Wang C, Qi L, Wen L, Zhang C, Yao C. Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation. Bone Research 2022, 10: 42. PMID: 35624094, PMCID: PMC9142495, DOI: 10.1038/s41413-022-00210-3.Peer-Reviewed Original ResearchToll-like receptorsSystemic chronic inflammationBone lossGut microbiotaSystemic inflammationChronic inflammationBone metabolismLow-grade systemic chronic inflammationActivation of TLRsInflammation-induced osteoclastogenesisOsteoclastic bone lossExpansion of CD4Low bone massSubsequent bone lossInflammatory cytokinesBone massT cellsInflammationOsteoclast differentiationBone marrowMyeloid-biased hematopoiesisImmune systemHematopoietic stem cellsSingle-cell RNA sequencingMice
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 rolePathogenesisLADADiseaseToll-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 autoantigenA predictive CD8+ T cell phenotype for T1DM progression
Wong FS, Wen L. A predictive CD8+ T cell phenotype for T1DM progression. Nature Reviews Endocrinology 2020, 16: 198-199. PMID: 32051538, PMCID: PMC8258660, DOI: 10.1038/s41574-020-0330-3.Peer-Reviewed Original Research
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 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 cells
2014
IRAK-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
2012
Type 1 diabetes therapy beyond T cell targeting: monocytes, B cells, and innate lymphocytes.
Wong F, Wen L. Type 1 diabetes therapy beyond T cell targeting: monocytes, B cells, and innate lymphocytes. The Review Of Diabetic Studies 2012, 9: 289-304. PMID: 23804267, PMCID: PMC3740697, DOI: 10.1900/rds.2012.9.289.Peer-Reviewed Original ResearchConceptsInnate lymphocytesB cellsT cell targetingNatural killer cellsRecent clinical trialsPathogenesis of T1DType 1 diabetesType 1 diabetes therapyKiller cellsSpecific therapyClinical trialsT cellsDisease processDiabetes therapyMultifactorial diseaseCell pathwaysMultiple cell typesDiabetesT1DLymphocytesTherapyMonocytesDiseaseSuitable targetCell typesThe Dual Effects of B Cell Depletion on Antigen-Specific T Cells in BDC2.5NOD Mice
Xiang Y, Peng J, Tai N, Hu C, Zhou Z, Wong FS, Wen L. The Dual Effects of B Cell Depletion on Antigen-Specific T Cells in BDC2.5NOD Mice. The Journal Of Immunology 2012, 188: 4747-4758. PMID: 22490442, PMCID: PMC4361183, DOI: 10.4049/jimmunol.1103055.Peer-Reviewed Original ResearchConceptsB-cell depletionCell depletionT cellsB cellsAntigen-specific T cellsAg-specific T cellsBDC2.5 T cellsDiabetogenic T cellsRegulatory T cellsT cell responsesB-cell reconstitutionB-cell regenerationT-cell phenotypeImmune regulatory functionsFuture clinical protocolsΒ-cell lossMultiple injection protocolsAutoimmune diabetesRituximab therapyCytokine profileDiabetic patientsCell reconstitutionTherapeutic effectPreclinical studiesHuman CD20