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1、Innate Immune SystemmonocytemonocytemacrophagemacrophagebacteriabacteriaThemostancientdefensePhysical&chemicalbarriersandcellularlineRecognitionbytheinnateimmunesystemsetsthestageforaneffectiveadaptiveimmuneresponse.机体在种系发生和进化过程中机体在种系发生和进化过程中逐渐形成的一种天然免疫防御逐渐形成的一种天然免疫防御功能，构成机体抵御病原生物功能，构成机体抵御病原生物入侵的第一道
2、防线入侵的第一道防线. . Innate immuneThe evolution of immune systemConservedsignallingininnateimmunityinDrosophilaandmammals.固有免疫系统的组成固有免疫系统的组成屏障屏障细胞细胞分子分子皮肤黏膜屏障：皮肤黏膜屏障：物理、化学、微生物物理、化学、微生物血血-脑屏障、血脑屏障、血-胸腺屏障胸腺屏障血血-胎屏障、气胎屏障、气-血屏障血屏障单核单核-巨噬细胞、中性粒细胞、树突状细巨噬细胞、中性粒细胞、树突状细胞、胞、T 细胞、细胞、NK细胞、细胞、NKT细胞、细胞、B1细胞、肥大细胞、嗜碱性粒细胞、
3、嗜细胞、肥大细胞、嗜碱性粒细胞、嗜酸性粒细胞、酸性粒细胞、nuocyte等。等。抗菌肽、溶菌酶、急抗菌肽、溶菌酶、急性期蛋白、补体、细性期蛋白、补体、细胞因子和黏附分子、胞因子和黏附分子、1、固有免疫屏障、固有免疫屏障(1) The Epithelial Layer: The initial barrier to infectionOuter body surfaceKeratin barrierEpithelial cell sheddingDryness epidermiswithkeratinPhysical (mechanical) defense of skinInnerbodysu
4、rfacesMucuslViscouslProtectsunderlyingcellslContainsantimicrobialfactorsLysozymeConstantfluidflowlTearslSalivalIntestinalperistalticlUrineproductionandurinationlVaginalsecretionslMucociliaryclearanceEpithelialcellsheddingPhysical (mechanical) defense of MucosaMucosal Tissuesthese surfaces are consta
5、ntly exposed to bacteria and other organismsSebum,unsaturatedfattyacidsl“antimicrobiallipids”LowpHlSkin(pH3-5)lStomach(pH1.53)lVagina(pH35)lUrine(pH6)9Chemical defenseTLRMicrobial Products(LPS, PG, etc)Antimicrobial PeptidesCytokinesExpresstoll-likereceptorsthatrecognizespecificPAMPProduceantimicrob
6、ialpeptides(AMP):killmicrobesSecretepro-inflammatorycytokines:alertthehostImmune function of epithelial cellsImmune system cells in the lamina propria and in the epithelial layerIntraepithelial lymphocytes (adaptive immunity)Three places where IgA can neutralize antigensSecretoryIgA(adaptiveimmunity
7、)Commensalspeciesarenonpathogenicmicroorganismsthatprotectepitheliumbycompetingwithpathogensfornutrientsandattachmentsites.Epithelium is protected by a flora of nonpathogenic microorganisms (commensal species)Skin Tongue EsophagusRespiratory tract and head outer ear, eye, mouth, oropharynx, nasophar
8、ynx Sterile sites: middle ear, brain, lower respiratory tract (trachea, bronchiole, lung)Gastrointestinal tract esophagus, stomach, small intestine, large intestineGenitourinary system anterior urethra, vagina Sterile sites: bladder, cervix, uterusSkinSites of human body that the normal flora microb
9、es colonizeThere are about 500-1000 microbial species living in healthy human gutThe Gut Microbiome Thehumanintestinalmicrobiotaiscomposedof1013to1014bacteriawhosecollectivegenome(microbiome)containsatleast100timesasmanygenesasourowngenome,atleasttentimesasmanycellsashumanbody.Normal flora may aid t
10、he host in several waysAid in digestion of foodProtect the host from colonization with pathogenic microbes.Help the development of mucosa immunity ThismaycauseinflammationandbleedingAntibiotics can make you sick by killing the commensal bacteria and allowing a opportunistic organism to invadeThe bar
11、rier function of the intestinal epithelium.Nature.2012Sep13;489(7415):231-41.1.Physical barrier of the epithelial layer 2.Mucus/cilia to remove particles (lung, intestines)3.Acid pH4.Anti-microial peptides secreted by some epithelial cells (small intestines, small airways of lungs)5.surfactant-Aand-
12、Dproteinsopsonizepathogensforenhancedphagocytosis(lung)6.Commensal bacteria (compete with pathogenic bacteria)7.Secretory IgA (adaptive immunity)8.Intraepithelial lymphocytes (adaptive immunity) (2) 体内特殊生理屏障血-胎屏障血脑屏障血脑屏障血脑屏障 血血- -脑屏障由软脑膜、脉络丛的脑毛细血管壁和包在壁外的星状胶质细脑屏障由软脑膜、脉络丛的脑毛细血管壁和包在壁外的星状胶质细胞形成的胶质膜共同组成。
13、胞形成的胶质膜共同组成。 血血- -胎屏障胎屏障 胎盘屏障由母体子宫内膜的基蜕膜和胎儿绒毛膜共同组成，能够有效胎盘屏障由母体子宫内膜的基蜕膜和胎儿绒毛膜共同组成，能够有效防止母体内的病原体及其毒性代谢产物进入胎儿体内。防止母体内的病原体及其毒性代谢产物进入胎儿体内。 其它屏障其它屏障 人体的胸腺、睾丸等部位存在屏障结构。人体的胸腺、睾丸等部位存在屏障结构。2、固有免疫细胞、固有免疫细胞PhagocyteNKILLs（固有样淋巴细胞）（固有样淋巴细胞）DC MCBasophil Eosinophil T细胞细胞 NKT细胞细胞 B1细胞细胞Monocyte-macrophageNeutrophi
14、lRecognition of an infection once it gets past the epithelial barrier单核巨噬细胞 腹腔巨噬细胞腹腔巨噬细胞粘附于玻璃表粘附于玻璃表面黏附性面黏附性高尔基体发达，高尔基体发达，线粒体丰富线粒体丰富分化过程中体积增大、细胞器增多、伪足更多、吞噬能力增强、分化过程中体积增大、细胞器增多、伪足更多、吞噬能力增强、产生更多水解酶、分泌大量可溶性因子。产生更多水解酶、分泌大量可溶性因子。单核细胞是白单核细胞是白细胞中体积较细胞中体积较大，蹄状核大，蹄状核ProfessionalphagocyticcellsNeutrophilMastc
15、ellMonocyteMacrophageDCMonocyte-bloodHistiocytesconnectivetissueKupffercellsliverMesangialcellskidneyMicroglialcellsbrainAlveolarmacrophages/DustcellslungPAMPPRR固有免疫细胞固有免疫细胞病原体病原体吞噬吞噬靶细胞裂解靶细胞裂解炎症反应炎症反应天然免疫细胞的效应天然免疫细胞的效应（1）吞噬杀伤病原体3个阶段：识别个阶段：识别recognition、吞噬、吞噬ingestion、消化、消化digestionM细胞功能细胞功能Opsonins
16、 and Phagocytic receptorsOpsonins Complementcomponents(C3b)Collectins(mannose-bindinglectin)AntibodiesPhagocytic receptorsReceptorsforopsonins(complementreceptors,Fcreceptors)Patternrecognitionreceptors(mannosereceptor,etc.)ReceptorsforapoptoticcellsM细胞功能细胞功能Surface receptors of macrophagesToll-like
17、 receptorsToll样受体样受体Mac-1、CR3Fc受体受体M细胞功能细胞功能Fc receptorsM细胞功能细胞功能Fc receptors; a cell- and ligand-specific familyFc receptors exist in different “flavors” on the surface of distinct immuno cells. As their names are suggesting they all bind Fc regions of specific immunoglobulin classes and contribute
18、 to the elimination of pathogens. NK cells specifically express Fc RIII.Staphylococcal Protein A Inhibits Phagocytosis by Blocking FcM细胞功能细胞功能Figure 8-21What is happening in phagolysosomes? M细胞功能细胞功能Oxidative attack via ROS & RNS:generated by NADPH phagosome oxidase (phox) enzyme complexThe oxygen c
19、onsumed by phagocytes to support ROS production by the phox enzyme is provided by the respiratory burst (吞噬细胞吞噬病原体后有氧代谢活跃，短时间内耗氧量显著增加，这种现象称为呼吸爆发呼吸爆发）M细胞功能细胞功能Reactive Oxygen IntermediatesReactive Oxygen IntermediatesLipid Peroxidation Lipid Peroxidation Membrane, Protein and DNA DamageMembrane, Prot
20、ein and DNA DamageH2O2O2-OH-M细胞功能细胞功能NO pathway yield NO L-Aginine + 1/2O2 Citrulline + NO yield Nitric peroxide (过氧化氮) free redical. NO + O2 - ONOO-inducible nitric oxide synthetase (iNOS)M细胞功能细胞功能M细胞功能细胞功能Mac-1(CD11b/CD18,M2,orCR3)Receptors for apoptotic cellsThestepsofefficientapoptoticcellcleara
21、nce.Find-me and eat-me signals and some phagocyte receptors前列腺素E白三烯B4PAF磷脂酶过氧化物（2）介导炎症）介导炎症：分泌炎症介质，参与炎症：分泌炎症介质，参与炎症M细胞功能细胞功能Figure 1-14MacrophagesengulfbacteriaandproduceinflammatorycytokinesM细胞功能细胞功能(3)免疫调节功能Activated macrophages secrete numerous pro-inflammatory cytokines and chemokinesM细胞功能细胞功能(4
22、)抗肿瘤作用膜融合，胞内溶酶体作用膜融合，胞内溶酶体作用蛋白水解酶、溶细胞素、蛋白水解酶、溶细胞素、TNF-ADCC肿瘤肿瘤细胞细胞M细胞功能细胞功能（1 1）单核巨噬细胞是专职抗原提呈）单核巨噬细胞是专职抗原提呈）单核巨噬细胞是专职抗原提呈）单核巨噬细胞是专职抗原提呈细胞（细胞（细胞（细胞（APCAPC）。）。）。）。 （2 2）加工处理外源性抗原和内源）加工处理外源性抗原和内源）加工处理外源性抗原和内源）加工处理外源性抗原和内源性抗原，具有免疫原性的小分子肽段性抗原，具有免疫原性的小分子肽段性抗原，具有免疫原性的小分子肽段性抗原，具有免疫原性的小分子肽段与与与与MHCMHC分子结合形成肽分
23、子结合形成肽分子结合形成肽分子结合形成肽MHCMHC复合复合复合复合物表达于细胞表面，供物表达于细胞表面，供物表达于细胞表面，供物表达于细胞表面，供T T细胞识别。细胞识别。细胞识别。细胞识别。 （3 3）单核巨噬细胞）单核巨噬细胞）单核巨噬细胞）单核巨噬细胞B7B7分子与活化分子与活化分子与活化分子与活化T T细胞表达的细胞表达的细胞表达的细胞表达的CD28CD28作用，提供作用，提供作用，提供作用，提供T T细细细细胞活化第二信号。胞活化第二信号。胞活化第二信号。胞活化第二信号。(5)加工处理提呈抗原，启动特异性免疫应答加工处理提呈抗原，启动特异性免疫应答M细胞功能细胞功能分泌分泌IL-1
24、IL-6IL-12TNF-a aIL-8GM-CSF细胞因子细胞因子酶酶其它因子其它因子杀伤杀伤肿瘤细胞肿瘤细胞抗原抗原呈递作用呈递作用前列腺素白三烯补体成分纤维蛋白结合蛋白凝血因子溶菌酶酸性水解酶赖氨酸酶酯酶胶原蛋白酶弹性纤维蛋白酶免疫调节作用免疫调节作用吞噬并杀吞噬并杀伤伤病原微生物病原微生物 巨噬细胞的功能M细胞功能细胞功能.Mantovani A Blood 2006;108:408-409M2s refer to diverse forms of M2 activation. M细胞亚群细胞亚群Macrophage subsetsKey properties and function
25、s of polarized macrophages Macrophage recruitment. Distinct macrophage subsets regulate inflammation and wound healing. In situ macrophage proliferation. Arecentdiscoveryhasshownthat,contrarytopreviousthinking,macrophagescanenterthecellcycleandproliferatelocally.Thusfar,insituproliferationhasbeensho
26、wntobespecificforThelper2(TH2)-typeresponsestoworms. Cell surface markers commonly used in macrophage research中性粒细胞(Neutrophil)在普通光学显微镜下观察Giemsa染色血涂片，中性粒细胞呈淡藕荷色，多叶核，胞浆中含有大量的细胞颗粒。透射电镜下其胞浆颗粒清晰可辨。一般特性一般特性1.具有较强的趋化作用和明显的吞噬能力,主要对抗胞外菌的感染。2.无需激活即能够发挥强大的杀菌作用,产生的过氧化氢又可与卤化物、髓过氧化物酶（myeloperoxidase，MPO）组成MPO杀菌系
27、统。3.在局部引发感染时，可迅速发挥吞噬杀伤和清除作用。无抗原提呈作用。Neutrophil receptors that are important for phagocytosisPresence of neutrophils in tissue sites (not blood) is a sign of acute inflammation中性粒细胞主要膜分子中性粒细胞主要膜分子补体受体：CR1、CR3和CR4Fc受体：lgGFc受体（FcR/）其他膜分子：LFA-1、IL-8R等Theinflammation中性粒细胞是首先到达感染部位的效应细胞中性粒细胞是首先到达感染部位的效应细胞
28、The phases of various leukocytes to the infection siteLeukocyte recruitment to sites of inflammationor DC2、固有免疫细胞、固有免疫细胞PhagocyteNKILLs（固有样淋巴细胞）（固有样淋巴细胞）DC MCBasophil Eosinophil T细胞细胞 NKT细胞细胞 B1细胞细胞Monocyte-macrophageNeutrophil过敏性疾病过敏性疾病抗原的处理与提呈抗原的处理与提呈(2)NK 细胞细胞 ( Natural Killer cells )大大颗颗粒粒淋淋巴巴细细
29、胞胞：占占外外周周血淋巴细胞总数的血淋巴细胞总数的10-15%.体体积积较较大大，胞胞浆浆含含有有大大的的嗜嗜苯苯胺胺颗颗粒粒。不不表表达达特特异异性性抗抗原原识识 别别 受受 体体 TCR（ TCR ORTCR OR CD3）或或BCR( ORCD19)。NK细胞基本概念细胞基本概念FcR:recognizeantibodycoveredcell-ADCCThe biological functions of NK cells.Science.2011Jan7;331(6013):44-9.NK细胞基本概念细胞基本概念Multiple sites for NK-cell developmen
30、t.NatRevImmunol.2007Sep;7(9):703-14.Gut,Brain,UterusNK来源于骨髓造血干细胞。主要分布于外周血和肝脏。NK细胞的来源和分布细胞的来源和分布Factorsthatinfluencethedevelopment,homeostasisandsurvivalofNKcellsNatRevImmunol.2011Aug26;11(10):645-57.IL-15在NK细胞发育分化的整个过程中起重要作用.NK细胞的分化及亚群细胞的分化及亚群RequirementsfortranscriptionfactorsinNKcelldevelopmentand
31、function.AdvImmunol.2011;109:45-85.NK细胞的分化及亚群细胞的分化及亚群Phenotypic markers of developing NK cells in the mouseCD16 FcR NK1.1 in mice or CD56 in humans NK细胞的分化及亚群细胞的分化及亚群MurineNKcellssubset(1)CD27/CD11bCD11bloCD27loCD11bloCD27hiCD11bhiCD27hiCD11bhiCD27lo(2)NK1.1/DX5(1)CD56CD56bright:占外周血NK10%，为中间过渡分化细胞，
32、以分泌细胞因子为主。CD56dim:占外周血NK90%，为终末分化细胞，以杀伤功能为主。HumanNKcellssubsetNK细胞的分化及亚群细胞的分化及亚群CD56brightnaturalkiller(NK)cellsarethemajorproducersofNK-derivedcytokinesfollowingactivationofmonocytes.NK细胞的分化及亚群细胞的分化及亚群HumanNKcellssubset(2)CD27人外周血NK细胞多为CD27lo,这些均为CD56dim。CD56bright是CD27hiNK细胞主体.(3)NKp46人和鼠NK细胞分化及亚群
33、的统一:前体阶段:CD122+NKp46-iNKR-未成熟阶段:CD122+NKp46+iNKR-成熟阶段:CD122+NKp46+iNKR+CD107ahiNKCD107aLoNKNK细胞的分化及亚群细胞的分化及亚群Recognition mechanism of NK cellsKAR & KIRl识别非HLA-I类分子配体是杀伤活化性受体（killer activating receptor, KAR）l识别HLA-I类分子的受体，在生理状态下抑制性作用为优势，为杀伤抑制性受体（Killer inhibitory receptor, KIR）NK细胞的的识别受体细胞的的识别受体ITIM：
34、immunoreceptor tyrosine-based Inhibitory motif ITAM：immunoreceptor tyrosine-based activation motif NK Receptors bind with class MHC molecules:-KIR(killerimmunoglobin-likereceptors):Numberofimmunoglobin-likedomain:KIR2D/KIR3DCytoplasticregion:longer-KIR2DL/KIR3DL(ITIM),inhibitoryreceptorshorter-KIR2D
35、S/KIR3DS,non-covalentcombinationwithDAP-12(ITAM),activatingreceptor-KLR(killerlectin-likereceptor):HeterodimerofCD94&NKG2(Ctypelectin)CD94:shortcytoplasticregion,nosignaltransmissionNKG2A:ITIMincytoplasticregion-CD94/NKG2A,inhibitoryreceptorNKG2C:nosignaltransmission,bindwithDAP-12(ITAM)-CD94/NKG2C,
36、activatingreceptorNK细胞的的识别受体细胞的的识别受体NK receptors bind with non class MHC molecules NKG2D:ExpressmainlyonthesurfaceofNKandTNosignaltransmissionNon-covalentbindingwithDAP-10(ITAM)MHCclasschain-relatedmoleculesA/B(MICA/B) Natural cytotoxic receptor(NCR):NKp46,NKp30,NKp44IgSFBindwithothermolecules(ITAM)
37、NK细胞的的识别受体细胞的的识别受体Killer activatory receptor(KAR)Killer inhibitory receptor(KIR) KIR: KIR2DS, KIR3DS KLR: CD94/NKG2C NKG2D NKp46 NKp30 NKp44NCRKIR2DL, KIR3DLCD94/NKG2ABind class I HLAmoleculesFunctionBind non-class I HLA molecules Receptors associated with killer activation and killer inhibition on
38、NK cellsNK细胞的的识别受体细胞的的识别受体NK细胞对靶细胞的识别模式 1. “丢失自我丢失自我”识别模式识别模式 是指杀伤抑制受体与MHCI类分子结合可以抑制NK细胞的杀伤功能，并将任何缺乏MHCI类分子的细胞作为靶细胞处理。被病毒感染的细胞或肿瘤细胞缺失MHCI类分子，NK细胞由此被激活而发挥杀伤功能。NK细胞的的识别机制细胞的的识别机制NK cells express “sensing” receptors for self-MHC class I NK细胞的的识别机制细胞的的识别机制Target killing by NK cellsNK细胞的的识别机制细胞的的识别机制 2.
39、“压力诱导压力诱导”识别模式识别模式是指NK细胞活化性受体NKG2D分子能识别多种肿瘤细胞表面的MICA分子。MICA分子在转录时需要热休克因子（HSF）的参与，而HSF通常需要在病毒感染、恶性转化和炎性反应等压力诱导下才能发挥转录表达作用，一旦机体受到此类压力诱导，HSF将促进MICA等分子的表达，从而被NKG2D所识别，激活NK细胞，发挥杀伤功能。NK细胞的的识别机制细胞的的识别机制NatRevImmunol.2012Mar22;12(4):239-52.NK细胞的的识别机制细胞的的识别机制 1.1.释放穿孔素释放穿孔素/ /颗粒酶颗粒酶（1）穿孔素：在钙离子存在的条件下，可在靶细胞的细胞
40、膜上形成多聚穿孔素“孔道”，使水和电解质迅速进入细胞内，导致靶细胞崩解死亡。（2）颗粒酶（丝氨酸蛋白酶）：可循穿孔素在靶细胞上形成的孔道进入靶细胞，通过激活凋亡相关的酶系统而导致靶细胞凋亡。NK细胞的杀伤机制细胞的杀伤机制NK细胞的杀伤机制细胞的杀伤机制2. 表达表达FasL活化后NK细胞（FasL）靶细胞（Fas）形成Fas三聚体胞浆内的死亡结构域相聚成簇与Fas相关死亡结构域蛋白结合募集和激活caspase8caspase8级联反应导致靶细胞凋亡。FADD (Fas-Associated Death Domain protein) NK细胞的杀伤机制细胞的杀伤机制3.分泌分泌TNF-TNF
41、-靶细胞（I型TNF受体）结合形成TNF-R三聚体胞浆内的死亡结构域相聚成簇激活caspase8导致靶细胞凋亡。DED(Deatheffectordomain)NK细胞的杀伤机制细胞的杀伤机制Molecules involved in apoptosisTumornecrosisfactorreceptor(TNFR)superfamily:Fas(CD95)TNFR(IandII)Ligands:InduceapoptosisFasL(CD96L)TNFand (Lymphotoxin LT+)TRAIL(TNF-relatedapoptosisinducingligand)Bcl-2fam
42、ilyBcl-2,Bcl-xLInhibitapoptosisBax,BadPro-apoptoticNK细胞的杀伤机制细胞的杀伤机制4. 抗体依赖性细胞介导的细胞毒作用抗体依赖性细胞介导的细胞毒作用 （antibody-dependentcell-mediatedcytotoxity,ADCC）NK细胞（IgGFc受体、FcR），识别杀伤与IgG抗体特异性结合的肿瘤或病毒感染细胞。NK细胞的杀伤机制细胞的杀伤机制. ADCC as a therapeutic means to kill tumor cells2、固有免疫细胞、固有免疫细胞PhagocyteNKILLs（固有样淋巴细胞）（固有
43、样淋巴细胞）DC MCBasophil Eosinophil T细胞细胞 NKT细胞细胞 B1细胞细胞Monocyte-macrophageNeutrophil过敏性疾病过敏性疾病抗原的处理与提呈抗原的处理与提呈Innate-like lymphocytes (ILL) are at the X-road of innate and adaptive immunity; they express receptors commonly found on the surface of NK cells, such as members of the NKG2 family and the NK l
44、ineage receptor NK1.1, as well as rearranged BCR or TCR ( but with very little diversity). ILL do not undergo clonal expansion before responding effectively to antigen. CharacteristicsofB-1andB-2cellsB-1 B细胞细胞B-1细胞抗原受体种类很少，抗抗原原识识别别谱谱狭狭窄窄。它们识别的抗原主要包括：某些细菌表面共有的TI-2TI-2型型多多糖糖抗抗原原，如肺炎球菌荚膜多糖(磷酸胆碱)和葡聚糖等；G
45、-菌表面共有的TI-1TI-1型多糖抗原型多糖抗原，如脂多糖；某些变性的自身抗原变性的自身抗原，如变性Ig、ssDNA。B-1细胞接受上述抗原刺激后产生的抗体，可对多种细菌和多种变性自身抗原起作用，缺缺乏乏严严格格特特异异性性，这在机体抗感染免疫和维持自身稳定过程中具有重要作用。抗原识别谱抗原识别谱B-1细胞应答特点B-1细胞可通通过过表表面面抗抗原原受受体体，直直接接与与相相应应多多糖糖抗抗原原配配体体交交联联结结合合而而被被激激活活，IL-5、IL-9等等细细胞胞因因子子作作为为细细胞胞活活化化第第二二信信号号，可协助和增强TI-2型多糖抗原对B-1细胞的激活作用和分泌功能；B-1细胞在接
46、受相应多糖抗原刺激后，48小小时时之之内内即即可可产产生生以以IgM为为主主的的低低亲亲和和性性抗抗体体，这对机体早期抗感染免疫和清除变性自身抗原具有重要作用；B-1细胞在增殖分化过程中不发生不发生Ig类别转换类别转换，每个B-1细胞克隆只能产生一种类型Ig；B-1细胞不产生免疫记忆不产生免疫记忆，再次接受相同抗原刺激后，其抗体效价与初次应答时无明显改变。Comparison of B-1 and B-2 B cell propertiesPropertyB-1 cellsB-2 cellsN regionsFewExtensiveV region repertoireRestrictedDi
47、verseLocationPeritoneum/pleuraEverywhereRenewalSelf renewal in situBone marrowSpontaneous Ig productionHighLowIsotypesIgMIgM/G/A/D/ECarbohydrate specificityYesRarelyProtein specificityRarelyYesNeed T cell helpNoYesSomatic hypermutation of IgNoHighMemory developmentNoYesYes RarelyRarely YesNo YesCarb
48、ohydrate specificityProtein specificityNeed T cell helpSpecificity & requirement for T cell help suggests strikingly different typesof antigens are seen by B-1 and B-2 B cellsT细胞细胞组织分布组织分布1.表达TCR-CD3复合物的T细胞称为T细胞。2.主要分布于黏膜及皮下组织，在粘膜免疫过程中可能起重要作用表面标志和特征表面标志和特征1.T细胞表面标志与T细胞大致相同，但多为CD4-、CD8-双阴性，少部份为CD8单阳性
49、2.T细胞，其表面抗原受体缺乏多样性，抗原识别谱狭窄。3.就功能而言，T细胞应属非特异免疫细胞，而不是特异性免疫细胞。 T cells mature in the thymusDNcellsincludeprecursorsthatwillgenerateaminorityofTcellsthatexpresstheTCR(neverexpressCD4orCD8co-receptorsevenasmatureTcellsintheperiphery)andamajorityofcellsthatwillexpressaTCRtogetherwitheitherCD4orCD8.Tcellsd
50、onotundergotheself-MHCrestrictedselectionprocess.DNDPSP1.Agrecognitionby-TcellsusuallydoesnotrequireMHCpresentation,occursdirectly(similartoantibody);detailed3-Dstructureof-TCRmorecloselyresemblesantibodythan-TCR2.DirectrecognitionofTCR-ligandwithoutrequirementofantigenprocessingallowsforrapidrespon
51、seT细胞细胞抗原识别谱1.感感染染后后产产生生的的热热休休克克蛋蛋白白或或表表达达于于受受感感染染细细胞胞表表面面的的热热休克蛋白；休克蛋白；2.感感染染后后异异常常表表达达于于受受感感染染细细胞胞表表面面的的脂脂类类抗抗原原-CD1分分子子复合物复合物；3.某某些些病病毒毒蛋蛋白白或或表表达达于于受受感感染染细细胞胞表表面面的的病病毒毒蛋蛋白白，如如疱疹病毒和牛痘病毒糖蛋白等；疱疹病毒和牛痘病毒糖蛋白等；4.分分枝枝杆杆菌菌产产生生的的小小磷磷酸酸化化非非肽肽分分子子，如如磷磷酸酸糖糖和和核核苷苷酸酸衍生物。衍生物。T细胞细胞生物学功能1.具具有有抗抗感感染染、抗抗肿肿瘤瘤作作用用，可识别
52、杀伤某些病毒和胞内寄生菌感染的靶细胞，及表达热休克蛋白和异常表达CD1分子的靶细胞。2.免疫调节：激活后分泌多种细胞因子参与免疫调节，介导炎症反应。3.维持免疫耐受natural killer T cellsnatural killer T cells介于介于NKNK和和T T细胞之间，共细胞之间，共表达表达NKNK细胞表面细胞表面分子分子NK1.1NK1.1和和TCR-CD3TCR-CD3复合体复合体分子的分子的T T细胞，亦称细胞，亦称NK1.1+TNK1.1+T细胞细胞（19871987年）。年）。CD1d-restrictednaturalkillerTNKT细胞 发育途径：NKT细胞
53、具有胸腺内和胸腺外两种发育途径，肝脏可能是胸腺外主要的发育场所。成熟NKT细胞主要分布于骨髓和肝脏，此外在小肠固有层、脾脏和淋巴结也有少量的分布。NKT cell are mainly generated in the thymusDNDPSPNKTcellsaregeneratedinthethymusfromCD4CD8DNprecursorthymocytes.WhilemostofthethymocytesofthislineageneverexpressCD4orCD8,theirdifferentiationisCD1d/lipidligandrestricted.NKTNKT细胞
54、亚群：所有NKT细胞均是CD1d限制性的.是否表达TCR：Val4-Jal8+I型NKT细胞和Va14-Jal8-II型NKT细胞是否表达NK1.1：NK1.1+NKT和NK1.1-NKT小鼠NK1.1+NKT中少数为CD4+CD8-NKT细胞；大多数为CD4-CD8-NKT细胞。人NK1.1+NKT中少数为CD4+NKT细胞和CD8+NKT细胞；大多数为CD4-CD8-NKT细胞。1）NKT细胞表面细胞表面TCR缺乏多样性，识别抗原谱窄，主缺乏多样性，识别抗原谱窄，主要识别靶细胞表面由要识别靶细胞表面由CD1d分子提呈的糖脂类抗原。分子提呈的糖脂类抗原。2）不受）不受MHC限制。限制。Cel
55、lularlocationofCD1a,CD1b,CD1c,CD1dandcorrespondingCD1-restrictedT-cellsubsetsandlipidantigens.CD1 molecules 半乳糖神经酰胺半乳糖神经酰胺NKTNKT在在CD1dCD1d提呈抗原的刺激下被激活，并迅速产生提呈抗原的刺激下被激活，并迅速产生IL-4IL-4、IFNIFN、IL-10IL-10、IL-13IL-13等细胞因子，从而在抗肿瘤、抗感染、抑制自身免疫等细胞因子，从而在抗肿瘤、抗感染、抑制自身免疫性疾病及移植免疫中发挥重要的作用。性疾病及移植免疫中发挥重要的作用。半乳糖神经酰胺半乳糖神
56、经酰胺But,paradoxically,inothermodels2、固有免疫细胞、固有免疫细胞PhagocyteNKILLs（固有样淋巴细胞）（固有样淋巴细胞）DC MCBasophil Eosinophil T细胞细胞 NKT细胞细胞 B1细胞细胞Monocyte-macrophageNeutrophilRecognition of an infection once it gets past the epithelial barrierNuocytes represent a new innate effector leukocyte that mediates type-2 immu
57、nity.Type-2immunity:responsibleforprotectiveimmuneresponsestohelminthparasitesandtheunderlyingcauseofthepathogenesisofallergicasthma.Type-2cytokines:interleukinIL-4,IL-5andIL-13.Nuocytesexpandinvivoinresponsetothetype-2-inducingcytokinesIL-25andIL-33,andrepresentthepredominantearlysourceofIL-13durin
58、ghelminthinfection.InthecombinedabsenceofIL-25andIL-33signalling,nuocytesfailtoexpand,resultinginaseveredefectinwormexpulsionthatisrescuedbytheadoptivetransferofinvitroculturedwild-type,butnotIL-13-deficient,nuocytes.TranscriptionfactorRORiscriticalfornuocytedevelopment.Nature.2010Apr29;464(7293):13
59、67-70.NatImmunol.2012Jan22;13(3):229-36.ThenuocyteinthelungandInnateactivationofatype2response.AgroupofnewlydiscoveredcellsnuocytesMPPtype2-multipotentprogenitortype-2cellIh2s-innatehelper2cellsNHC-naturalhelpercellcanallbeactivatedbyIL-25and/orIL-33todriveTh2celldifferentiationandtype-2-associatedp
60、athology.3、固有性免疫分子指体表分泌液以及血浆和其它体液中能够识别或攻击病原体的指体表分泌液以及血浆和其它体液中能够识别或攻击病原体的可溶性分子。可溶性分子。抗菌肽抗菌肽antimicrobialpeptides溶菌酶溶菌酶lysozyme急性期蛋白急性期蛋白(acutephaseproteins,APP)脂多糖结合蛋白（脂多糖结合蛋白（LBP）血清淀粉样蛋白（血清淀粉样蛋白（SAP）甘露糖结合蛋白（甘露糖结合蛋白（MBP）C反应蛋白等（反应蛋白等（CRP）补体补体 细胞因子和黏附分子细胞因子和黏附分子Antimicrobial peptides1. size from 6-59 a
61、a residues & positive charge (cationic) (ex): humans defensins: 29-35 aa residues in length2. often work by disrupting microbial membranes3. produces a variety of intracellular effects such as inhibiting the synthesis of DNA, RNA, or protein, and activating antimcrobial enzymes4. attack not just bac
62、teria and fungi but virusesAcute phase proteinsAcute phase response (APR): the serum changesAPR proteins: their concentrations rose or fell(during the acute phase)Sites of injury or infection signals (proinflammatory cytokines: TNF- , IL-1, & IL-6 produced by phagocytes) stimulatingLiver: synthesis
63、of APR proteins Increase in the level of C-reactive protein & others (Mannose-Mannose-bindinglectinbindinglectin/MBL/MBL，Serumamyloidprotein/SAP,fibrinogenSerumamyloidprotein/SAP,fibrinogen)Summary and Review of Innate Immune Responses考核方式考核方式(1)Cell,Nature,Science,Natureimmunology,Immunity,Annurevimmunol,Natrevimmunol杂志2013年免疫学研究论文或综述.(2)忠实于原文(3)语言流畅(4)版面工整美观9月16日之前提交译文题目,课代表统计查重后调整文献.11月25日之前提交译文和原文的电子版,研究生试卷打印版.
