Chapter10Cell-mediatedimmunity

1.Definition

2.FunctionallydistinctTcellpopulations

3.Cell-mediatedimmunityincontext

4.DTH(delayedtypehypersensitivity

5.Effectormechanismsintracellularpathogens:bacteria

6.HowdoesCTLkillthetargetcell

7.ComparisonofTcandNKcell

8.Thebasicprocessandfeaturesofcell-mediatedimmunity

9.Biologicaleffectofcell-mediatedimmunity

1.Definition

Cellmediatedimmunity(orTcell-mediatedimmunity)isduetothe

directactionofTcells,andcanbetransferredbycells,which

distinguishesitfromhumoralimmunity,whichismediatedby,andcanbe

transferredby,antibodies.

2.FunctionallydistinctTcellpopulations

Tcellshavetwomajorroleswhicharecarriedoutbytwodistinct

subpopulations.Thelper(Th)cellshelpothercellscarryouttheir

functions,whilstTcytotoxic(Tc)cellsdirectlykillcellsinfectedwith

intracellularmicrobes.

BothTcandThcellsneedtointeractdirectlywiththecellstheyaregoing

tokill/helpandtheydothisthroughspecificrecognitionmechanisms.

ThisismediatedthroughinteractionwithMHCmoleculesonthesurface

ofthecellsbeingtargetedforhelporcytotoxicity.

MemoryTCells,Tm（記憶T細(xì)胞）

?Restingcell靜息期（GO期）

?Longevity壽命長(zhǎng)（不斷更新）

?Activatedeasily易激活（不需要協(xié)同刺激信號(hào)）

?Responsibleforimmunememory負(fù)責(zé)保持免疫記憶

RegulatoryTcells

?Anti-idiotypicTcells

?Thl,Th2,Th3,Trl

?CD4+25+Tcells

?CD8+gd-T-cells

?CD4CD8DoublenegativeTrcells

?NKTcells

?AnergicTcells

Peripherallymphoidtissuestrapantigen-

containingphagocyticcellsandconcentratecells

togethertopromotecell-cellcontact.Cell-cell

contactoccursatmanystagesofimmuneresponses.

Ab

Phagocyte

NominalantigenrecognitionbyTcells

效應(yīng)T細(xì)胞的MHC限制性

RolfZinkentagleandPeterDoherty

NobelPrize1996

T細(xì)胞-抗原提呈細(xì)胞間相互作用的MHC限制性。窗

3.Cell-mediatedimmunityincontext

TounderstandandappreciatethevariousfunctionalactivitiesofthedifferentTcell

subpopulations,itisimportanttofirstputthesecellsandtheirpropertiesintoa

relevantcontext.Antigenpresentingcells(APCs)initiallyprocessandpresent

microbialpeptidesinassociationwithMHCclassIImolecules.Thcellsrecognize

andareactivatedbyinteractionwiththesecells,andinturninfluenceAPCfunction

bydirectinteractionandcytokines.TheseAPCsmaythenpresentantigenmore

efficientlyinassociationwithMHCclassItoCTLsandclassIItoThcells.Specific

Thcellsactivatemacrophages(byreleaseofIFN丫);specificCTLskillinfectedcells

expressingviralantigensinassociationwithMHCclassI.

外來(lái)抗原的捕獲與遞呈

APC啟動(dòng)獲得性免疫應(yīng)答

樹突細(xì)胞

異物抗原

引流淋巴管

淋巴結(jié)

輸入淋巴管

摘出淋巴管

Fig.lAPCcaptureandpresentantigensandinitiateacquiredimmunity

Ofass11

witHvireil

PJGfOtidO

O1S-A

IC3FSOir>dir->otoviral

peQtiul。in2110da：

Fig.2Dendriticcells(DC)cmulitinned(licenseri)hyThIcellspresentnntigentoTc

viaMHCclass1.

ExplainationofFig.2

Dendriticcells(DC)conditioned(licensed)byThlcellspresentantigentoTcvia

MHCclassI.InteractionofspecificThJcellswithpeptide(e.g.fromavirusortumor

cellprotein)presentedinMHCclass〃ontheDCinvolvesadhesionmoleculesas

wellasbindingofB7toCD28.Thisseriesofinteractionsinducesexpressiononthe

ThlcellsofCD154whichthenbindsCD40ontheDC.Thistriggeringthrough

CD40,inthepresenceofcytokinesalsoreleasedbyThlcells,conditionstheDCto

presentantigeninMHCclassItopeptidespecificTcprecursorcells,inducingtheir

maturationintoTccells.

Inadditiontospecificallybindingappropriatelypresentedantigen,Thcellsalsohave

receptorswhichbindtothenonpolymorphicregionofMHCclassII,restrictingthese

cellstorecognizeonlypeptidespresentedonMHCclassIImolecules.This

interactionactivatesThcellstoproducecytokinesandtoproliferateanddifferentiate

intomemoryTcells.

Costimulationofantigenandco-receptor

activatedTandBcell*'.A.

SIGNAL1:

Antigen

Recognition

(±co-receptors)

Antigen-receptorandco-receptorligationareoften

insutticwntforproliferationandtheexpressionof?(1?clcxfunction

LowaffinityTcRbindingConformational

adhesionbef/reensignalsLFA-1changeinLFA-1

LFA-1&ICAM-1prolongsadhesion

Fig.3Antigen-receptorandco-receptorligationareofteninsufficientforproliferation

andtheexpressionofeffectofunction

SIGNAL2

CognateT-professionalAPCco-slimulatoryhteraction

Antigenrecognition

&co-receptorligation

inducesCD28onTcells

Signal1&signal2arerequiredforTcellclonalproliferation

anddifferentiationtoeffectorOEIIS

Fig.4CostimulationofThelpercellsbyprofessionalAPC

Inturn,theThcellprovidesessentialhelpforactivation,proliferationand

differentiationoftheantigenpresentingcell(e.g.dendriticcells,macrophagesandB

cells).ThcellsarealsosubdividedintoTh1andTh2cellsbasedontheircytokine

profilesandfunctionalactivity.

GMCSFTNF

TAF

Fig.5.MacrophageactivationbyCD4+injlammatotyTcells(Thl).

CytokinesreleasedbyThlcells,aswellassignalingthroughdirectcontactofcell

suffiicereceptors,increase:(a)fusionoflysozomesandphagosomes;(b)production

ofnitricoxideandoxygenradicalsforkillingpathogens:and(c)expressionofMHC

classIImoleculesandTNFreceptors.NotethatCD154/CD40interactionsarealso

importantinactivationofthemacrophage.

GZ1-OS尸GM-OS尸

IL-2ii_y

IRN-Yll--5

TNF<xll_-6

TTMF-pII--1O

TGF-p

Fig.6CytokineprofileofinflammatoryTcellsubset

AntibodiM(includingigE)

Fig.7SelectionofeffectormechanismsbyThlandTh2cells.

Inadditiontodeterminingvariouseffectorpathwaysbyvirtueoftheirlymphokine

production,ThJcellsswitchojfTh2cellsandviceversa

Table1RolesofinflammatoryThlcellcytokines

IL-3Growthofprogenitorhaemopoeticcells

GM-CSFMyelopoiesis

IL-2Tcellgrowth

IFN-yMacrophageactivation;

InductionofMHCclassII

InhibitionofTh2cells

CTLinduction

TNF-aMacrophageactivation

TNF-6Cytotoxicity

Macrophageactivation

Neutrophilactivation

4.DTH(delayedtypehypersensitivity遲發(fā)型超敏反應(yīng)

早期：活化的TDTH及活化的M力浸潤(rùn)為主，它們聚集在活化血管內(nèi)皮細(xì)胞周圍，并外滲

到局部組織

晚期：以簇狀上皮樣M。和巨細(xì)胞增生為主并伴有大量的纖維母細(xì)胞形成組織纖維以代替

膠原組織，形成纖維化的結(jié)節(jié)和肉芽腫。

5.Effectormechanismsintracellularpathogens：bacteria

InductionofCTLdifferentiation

Fig.8Th1細(xì)胞在抗胞內(nèi)病原體感染中的作用

活化的Th1細(xì)胞

TNF-pIL-2IL-3+GM-CSFTNF-p+MCFMCF+MIF

活化血管內(nèi)

殺傷慢性感

誘導(dǎo)T細(xì)胞誘導(dǎo)骨筋單皮細(xì)胞誘導(dǎo)使M?向感染

染附增殖核細(xì)胞分化灶聚集

M6滲出

Fig.9cytokinessecretedbyactivatedThIandtheirfunlions

CD41T活化——效應(yīng)性Th1細(xì)胞——分泌細(xì)胞因子

IL-2：促進(jìn)T細(xì)胞增殖

IFN-y：活化M6增強(qiáng)其表達(dá)MHC-II分了的表達(dá)

TNF-B：使血管內(nèi)皮細(xì)胞表達(dá)粘附因子，分泌趨化因子

Table2RolesofTh2cytokines

IL-3Growthofprogenitorhaemopoeiticcells

GM-CSFMyelopoiesis

IL-4Bcellactivationandgrowth

JgEisotypeswitch

InductionofMHCclassIL

Tcellgrowth

Macrophageinhibition

IL-5Eosinophilgrowth

IgAisotypeswitch

IL-6Bcellgrowth

Acutephaseproteinrelease

IL-10Inhibitsmacrophageactivation

InhibitsThlcells

TGF-BInhibitsmacrophageactivation

Thl

B7

漿細(xì)胞

Fig.10Bcellactivation(proliferationanddifferentiation)

Classswitching

IL-4alsoenhancesIgM,hiAgGAandm(/lgG1

Differentiationand

development

Mastcell

Eosinophil

EffectorfunctionsofTh2cells

AntiinflammatorypropertiesofTh2cells

MacrophageActivated

macrophage

LikeThcells,Tccellsalsospecificallybindappropriatelypresentedantigen,butthese

cellshavereceptorswhichbindtothenonpolymoiphicregionofMHCclassI,

restrictingthemtorecognizeonlypeptidespresentedonMHCclassImolecules.1c

cellskillvirusinfectedcellsbyinductionofapoptosis(programedcelldeath).

Fig.CTLrecognizepeptidesassociatedwithMHCclassImolecules.CD8bindsto

non-polymorphicMHCclassIstabilizingthisinteractionandenhancingkilling.

IL-2

活化.護(hù)增

Fig.doublesignalsforCD8+Tactivation

圖CD8+T細(xì)胞活化雙信號(hào)示意圖

Fig.specificsignalandcostimulativesignalintheactivationofTc

圖Tc活化的特異性信號(hào)和協(xié)同刺激

Fig.activationofTc

Tc細(xì)胞的活化

1.Stimulatorcell

2.Antigen-presenting

expressingclassIMHC

cellpresents

presentsantigen(?)

antigeninassociationvwith

toapre-cytotoxicTcoll

classIIMHCto

3.CD4*TcellCD4+Tcell

signaling

makescytokines

?PreCD8IFN

IL-2

etc

4.ProCTL

differentiatesto

1.CTLffecoytiizedantigenon

targotcell

2.CTLisactivaWd

3.AlethalHitisdelisredby

theCTLusingagents

auctiasperforinorgraozymcB

4TheCTL

fromtHotargu*cdI

5.Targetc9lldieo

t)yapoptoxis

Fig.Apoptosisinducedbyreleaseoflyticgranules.

Perforinspolymerizeinthemembraneleadingtopassageof^ranzymesintothecell.

(a)Lyticgranulescontainingperforinandgranzymesaccumulateatthepointof

contactofCTL(viaTCR/MHCandothermolecules)withvirusinfectedcell.(b)The

granulecontentsarereleased,theperforinpolymerizesandinsertsitselfintothe

infectedcellmembraneallowingentryofgranzymeswhichinduceapoptosis.

6.HowdoesCTLkillthetargetcell

CTL殺傷靶細(xì)胞的機(jī)制

①releaseperforinstothecellsurfaceandformpolyperforinchannelbytheaction

ofperforinpolymerase

②thereleaseddegradativeenzymeortoxinenterintothecellthroughtheformed

polyperforinchannel.

③releaseTNF-a/B,interferonyontothesuijaceoftargetcell,thebindingof

themwiththereceptorsassociatedwithtargetcellwillprovideanapoptosissignal.

(4)Fas/FasLinteractionscanalsoinducetheapoptosis.

FasL(CD95)

Fig.ApoptosisinducedbyFas/FasLinteractions.

CTLhavepreformedFasLintheirgranuleswhichisrapidlyexpressedontheir

surfacewhentheyattachviatheirTCRtothetargetcell.LigationofFasonthetarget

isanadditionalmechanismforinductionofapoptosisoftheinfectedcell.

(靶上Fas的連接是誘導(dǎo)受感染細(xì)胞的細(xì)胞凋亡的另一個(gè)機(jī)制)

凋亡信號(hào)活化信號(hào)

CTLA-4

B7-1

APC

CD8+T細(xì)胞活化——效應(yīng)性Tc細(xì)胞

特異性殺傷攜帶抗原的細(xì)胞穿孔素絲氨酸蛋白酶FasL-Fas蛋白誘導(dǎo)的凋亡

特點(diǎn)：

特異性殺傷作用

殺傷作用受MHC-I類分子限制

效應(yīng)性細(xì)胞Tc可連續(xù)殺傷靶細(xì)胞。

效應(yīng)：抗病毒免疫抗腫瘤免疫