调节性T细胞研究进展.ppt

调节性T细胞研究进展.ppt

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,调节性T细胞研究进展高晓明北京大学医学部2009.12.11苏州,ImmunityApril，2009,Tr1:

ProducingIL-10afterAgtriggeringNKT:

SecretIL-4afteractivationTh3:

ProduceTGF-bafterAgtriggeringTact（AnergicTcells）CD8+gd-TcellsCD4-CD8-Tcells,OthertypesofregulatoryTcells,Treg细胞的表型,nTreg和iTreg,Treg的免疫调节作用机制,Treg的临床应用前景,4,1,2,3,Treg细胞的表型,Tregs,CD25,Foxp3,TGF-,其他标志分子,Treg与CD25,经典实验一,Treg与CD25,经典实验二,Normalmouse,CD4+TcellseliminatedCD25+cells,Tcell-deficientmouse,AutoimmunediseasesThyroidStomachSalivaryglandLangerhansisletsAdrenalglandsOvariesOestes,CD4+CD25+Tregs在外周淋巴细胞中的比例,Th9,Th17,性联免疫失调综合征（IPEX）患者,Scurfy小鼠,Foxp3基因敲除小鼠,Treg与Foxp3,2022/10/15,IPEX,Immunedeficiency/dysregulationPolyendocrinopathyEnteropathy（OftenhaveAbagainstgutepithelium）X-linkedinheritance,PatientshavemutationsinFOXP3gene.TheysufferfrominflammatorydiseasessimilartothatseeninmicedeficientinCD4+CD25+Tregcells.,2022/10/15,IPEXOutside（ClinicalFindings）,Firstdescribedin1982byPowelletal.asasyndromeofdiarrhea,polyendocrinopathy,andfatalinfectionininfancy.NeonatalonsetdiabetesmellitusHypothyroidismEnteritis（diarrhea/villousatrophy）Hemolyticanemia&thrombocytopenia.DermatitisDermatitis（eczema）Deathby1-2yearsofage,2022/10/15,SkinDiseaseinIPEX,2022/10/15,IPEXInside（AutopsyFindings）,Pancreas:

isletsofLangerhansabsentwithlymphocyticinfiltratesIntestine:

villousatrophywithlyphocyticinfiltratesLiver:

CholangitisSpleen:

enlarged,Lymphnodes:

FollicularhyperplasiaThyroid:

LymphocyticinfiltratesLungs:

Consolidation/InflammationThymus:

Atrophy,（inflammatorydiseasessimilartothatseeninmicedeficientinCD4+CD25+nTregcells）.,2022/10/15,FOXP3Mutations,IPEXsyndrome-FOXP3deficiency,2022/10/15,PROLINE-RICHDOMAIN,ZINC-FINGER,LEUCINEZIPPER,FORKHEADDOMAIN,N,C,FOXP-3isthemastercontrolgeneforTregdevelopment,encodesanovelforkhead/wingedhelixtranscriptionfactor,2022/10/15,WhatdoesFOXP3do?

1PlaysanessentialroleinthedevelopmentandfunctionofCD4+CD25+Tregs,Foxp-3expressioninCD4+thymocytesisdetected3daysafterbirth2Mayfunctionasatranscriptionalrepressorofcytokinepromoters3Foxp3ishighlyenrichedinCD4+CD25+Tregsinthymusaswellasinperiphery4TargeteddisruptionofFoxp3genepreventsCD4+CD25+nTregdevelopmentandmicedeveloplethalinflammatorydisease（Scurfy）,SignalingPathways,TranscriptionFactors,andRegulatoryDNAElementsthatControlFoxp3Expression.（Josefowiczetal.,Immunity,2009）,Treg与TGF-,Nakamuraetal.,JEM,2001,CD4+CD25+Tregs高表达TGF-，特别是膜结合型TGF-,Treg与TGF-,TGF-1缺陷的CD4+CD25+Treg,Wild-typeCD4+CD25+Tcells,SCIDmouse,SCID+colitismouse,Transfer,动物模型中TGF-对Treg功能的影响,Treg与TGF-,TGF-缺陷的CD4+CD25+Treg在体内不能保护小鼠发生自身免疫病性结肠炎,TGF-1缺陷的CD4+CD25+Treg,Nakamuraetal.,JI,2004,wild-typeCD4+CD25+Tcells,Treg与TGF-,TGF-与CD4+CD25+Treg的诱导产生,Chenetal.,JEM,2003,TGF-andTCRcostimulationinducesFoxp3expressioninCD4+CD25-naiveresponderTcells.,Treg与TGF-,Zhouetal.,Immunity,2009,TheCytokineMilieuDeterminesCD4+TCellDifferentiationandConversion,Treg的其他标志分子,CTLA-4,CD39,4,2,Neuropilin-1expressiononregulatoryTcellsenhancestheirinteractionswithdendriticcellsduringantigenrecognition.Neuropilin-1isnotamarkerofhumanFoxp3+Treg.,IsolationoffunctionalhumanregulatoryTcells（Treg）fromtheperipheralbloodbasedontheCD39expression.（JImmunolMethods，2009）,OX40costimulationcanabrogateFoxp3+regulatoryTcell-mediatedsuppressionofantitumorimmunity.（IntJCancer，2009）,CTLA-4controloverFoxp3+regulatoryTcellfunction.,小结,Treg的基因表达有其特殊性：

信号转导相关基因（COS，SOCS-1，SOCS-2及SLAP130）；分泌性分子（IL-10，IL17，IL-35，MIP-1，MIP-1及ETA-1等）；细胞表面分子（CD2，OX40，CD25，CD122，Ly-6，Thy-1及GITR等）。

虽然这些分子中的一些或在一般活化态T细胞表达，或在Foxp3-的无能T细胞表达，但可能正是这样的基因组合保障了Treg的存活和低反应状态，且是其发挥免疫学功能的分子基础。

InthymusIL-2SpecificantigenstimulationFoxp-3expression,2022/10/15,Bonemarrow,Deletion,CD25+CD4+,CD4+,CD4+,Periphery,B,Mj,Effector,Thymus,Treg,Navecells,Selfantigen,2022/10/15,IL-2isrequiredfordevelopmentofCD4+CD25+nTregs,anti-IL-2treatmentearlyafterbirthleadstoautoimmunediseasesinadultsExpansionofnTresgsinthymusislikelyautoantigen-driven,2022/10/15,OVA-TCR-tg,OVA-TCR-tgRag-/-,不表达内源性TCR链,内源性TCR链大量表达,CD4+CD25+nTreg的产生依赖对抗原的特异识别,无CD25nTregs,产生OVA特异性CD25nTregs,2022/10/15,Probabilityofselection,AvidityofTCR-MHC-peptide,Positiveselection,Negativeselection,CD25+CD4+nTregs,HighaffinityinteractionwithMHC/selfpeptideisrequired,NaturallyoccurringTregs:

CD4+CD25+Foxp3+,MostFoxp3+thymicTreg（tTreg）cellsdifferentiatefromFoxp3-negativeCD4+SPthymocytes.,CD4+,Foxp3+Treg,Foxp3-,Foxp3-,TE,Tr1,Foxp3+nTreg,Foxp3+iTreg,胸腺,外周,TGF-,IL-10,TGF-binducestheexpressionofFoxp3inCD4+CD25-Tcells;RetroviraltransductionofFoxp3rendersCD4+CD25-TcellssuppressiveIL-10TreatmentofCD4+CD25-Tcellsmakesthemsuppressive,InductionofTregs1:

InductionofTregs2:

Treg-iTreg（Thsup）,CD25TregcellsconveyasuppressiveactivitytoconventionalCD