cell mediated immunityy

8/11/2019 Cell Mediated Immunityy

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CellMediated

Immune

Responses

Sitti Wahyuni,MD,PhD

DepartmentofParasitology,

MedicalFaculty,Hasanuddin University

1S.Wahyuni/lecture/immunology/S16/14/2012


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ActivationofTlymphocytes

adaptiveimmuneresponse

infection M cro es n ng ns ece s

Intraphagosom:microbes/protozoa

Intracytoplasmic:microbes(virus)



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Whatsi nalsareneededtoactivateT

lymphocytes Whatcellularreceptorsareusedtosenseand

HowarethefewnaiveTcellsspecificforany

effector Tcellsendowedwiththeabilitytoeliminatethemicrobe?

atmo ecu esarepro uce y ymp ocytesthatmediatetheircommunicationswithothercells suchasmacro ha esandBl m hoc tes?



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PhasesofTCellResponses

n gen ecogn onan ons mu a on RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation

Ro eo Constimu ation inTCe Activation

Responsesof TLymphocytestoAntigen&Constimulation Secretionofcytokines&expressionofCytokinesreceptors

Clonal Expansion

DifferentiationofNaiveTCellsintoEffector Cells

DevelopmentofMemoryTLymphocytes

DeclineoftheImmuneResponse

BiochemicalPathwaysofTcellActivation



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StepsintheactivationofTlymphocytes



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u RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation

Ro eo Costimu ation inTCe Activation

Responsesof TLymphocytestoAntigen&Constimulation Secretionofcytokines&expressionofCytokinesreceptors Clonal Expansion



DeclineoftheImmuneResponse

BiochemicalPathwaysofTcellActivation



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TheinitiationofTcellres onsesre uiresmulti le

receptorsontheTcellsthatrecognizeligands onAPCs: TCRrecognizesMHCassociatedpeptideantigens,

or coreceptorsrecogn zet e mo ecu es

AdhesionmoleculesstrengthenthebindingofTcellsto

APCs

Receptorsforcostimulators recognizesecondsignalsprovidedbytheAPCs

accesory molecule:

Functions:recognition,signaling&adhesion



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LigandreceptorpairsinvolvedinTcell



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TlymphocytesReceptor(TCR)

doneby:

Coreceptor(CD4orCD8)

:

aclonallydistributedreceptor(clonesofTcells

w eren spec c esexpress eren sconsistsofan chainanda chain



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bindingportion

theVandV



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CD3

c ain



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heterodimer , , .

chainisaa disulfidelinkedhomodimer

o e: s gna ng,w en e recogn zes

antigen,CD3and transduce thesignals



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TheexpressionoftheTCRcomplexrequires



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EverymatureMHCrestrictedTcellexpresses

eitherCD4orCD8 RecognizeMHCpartofpeptideMHCcomplex

onAPCs

CD4+

Tcells,whichfunctionascytokineproducinge perce s,recogn zem cro a an gens a are

displayedbyclassIIMHCmolecules

+ ,

lymphocytes(CTLs),recognizepeptidesderivedfromcytoplasmic microbesdisplayedbyclassIMHCmolecules.



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Antigenrecognitionandsignaltransduction



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Adisulfidelinkedheterodimer

ExpressedonasmallsubsetofnegativeTcells

5%ofallTcellsexpressthisformofTCR

consistofextracellularI likeVandCre ionsshortconnectingorhingeregions,hydrophobictransmembrane segments,and

shortcytoplasmic tails AssociateswithCD3and proteins



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inducedsi nalin event&secretionofc tokinesand

lysis oftargetcells. DonotexpressCD4orCD8

DonotrecognizeMHCassociatedpeptideantigens

NotMHCrestricted. Mayrecognizeantigensthatarefrequently

encounteredatepithelialboundariesbetweenthe.

Mayinitiateimmuneresponsestoasmallnumberofcommonmicrobesatthesesites



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withlowaffinity(becauseofnegative

Function:recognizetheirligands onAPCsand

.

Integrin isthemostimportantadhesion

mo ecu es



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alowaffinitystate.

partoftheinnateimmuneresponseto

infection:LFA1moleculesareconvertedtoahighaffinitystateandclustertogetherwithinminutes.

Bindwithintercellularadhesionmolecule1(ICAM1)onAPC



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cellsthatfunctiontogetherwithstimulation.

Therearetwoconstimulation moleculs:

on ce n o on s

CD40LexpressedonanantigenstimulatedTcell



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,

APCswhentheAPCsencountermicrobes.

cell

B7CD28 nteract ons sessent a or n t at ng

theresponsesofnaiveTcells

AbsenceofB7CD28interactionsisunabletoactivatetheTcells(anergy)



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,

theirreceptor(i.e.,CD28)isessentialforfullT.

ItispossiblethatCD28engagementamplifies

ofsignalsthatcomplementTCRsignals.



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Th r l f c tim lati n in T c ll activati n



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Vaccinationisa rocesstoinduceinflammationb killedmicrobes

SuchmicrobesarenotabletoinduceTcellactivation

AdjuvantisacomponentthataddedtovaccinetoactivatemacrophagesandotherAPCs

Inducingtheexpressionofcostimulators onAPCs

StimulatingtheAPCstosecretecytokinesthatactivateT

cells. Mostadjuvants areproductsofmicrobes(e.g.,killed

.



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+



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n gen ecogn onan os mu a on

RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation


Responsesof TLymphocytestoAntigen&Constimulation

Secretionofcytokines&expressionofCytokinesreceptors Clonal Expansion



DeclineoftheImmuneResponse BiochemicalPathwaysofTcellActivation



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Tlymphocytesbegintoproliferate,resultingin .

Providesalargepoolofantigenspecificymp ocytes romw c e ector ce scan e

generatedtocombatinfection



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+

specificforoneviralproteinantigenisabout1in105 106 lymphocytesinthebody.

Withinaweekaftertheinfection,asmanyas

10%to20%ofallthelymphocytesinthelymphoidorgansspecificforthatvirus.

Antigenspecificcloneshaveincreasedby

morethan10,000fold,withanestimateddoublingtimeofabout6hours.



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Thismayreflectdifferencesintheirfunctions.

CD8+ CTLsaree ector ce st att emse ves

killinfectedcells,andmanyCTLsmaybenee e to argenum erso n ecte ce s

CD4+ effector cellssecretecytokinesthat

activateothereffector cells



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Differentiation of Naive T Cells into Effector Cells

(e.g.,theactivationofgenesencoding+ +

proteins[inCD8+ CTLs]).

microbes.

ector ce s eavet eper p era ymp o organsandmigratetothesiteofinfection.



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+

Effector TcellofCD4Tl m hoc te

Respondtoantigenbyproducing:surfacemolecules(CD40L)thatwillbindtoCD40

expresse ma n yonmacrop ages, ymp ocy es,anddendritic cells)

cytokinesthatfunctionmainlytoactivatemacrop agesan B ymp ocytes

CD4+ helperTcellsmaydifferentiateintoTH1cells

producedistinctsetsofcytokinesthatperformdifferentfunctions.


Th l l i l d i h ff


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Themoleculesinvolvedintheeffector+


Th f ti f T 1 d T 2 b t f CD4+


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ThefunctionsofTH1andTH2subsetsofCD4+


diff b T 1 d T 2 b f


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differencesbetweenTH1andTH2subsetsof


h d ff f h l ll


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ThedifferentiationofnaiveCD4+ helperTcells

H

H

process

thestimulithat

receivewhenthey

antigens



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+

ProducedinactivationofCD8+ Tlymphocytes

ThedifferentiationofnaiveCD8+Tcellsinto

e ector CTLs saccompan e yt esynt es s

ofthemoleculesthatkillinfectedcells

CTLsareabletokillinfectedcellsexpressingtheantigen



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differentiatesintolonglivedmemoryTcells.

Foundinlymphoidtissues,inmucosal

arr ers,an nt ec rcu at on.

Memorycellsareapooloflymphocytes

waitingfortheinfectiontoreturn Whatkee smemor cellsaliveisunknown



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Memor Tcellsdonotcontinueto roducecytokinesorkillinfectedcellsbuttheymaydosorapidlyonencounteringtheantigenthatthey

.

Twosubsetofmemorycell:

Centralmemor cells, o ulatel m hoidtissuesandareresponsibleforrapidclonal expansionafterreexposuretoantigen.

mediaterapideffector functionsuponreintroductionofantigentothesesites.



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forlymphocyteactivationdisappear

aftertheinfectioniseradicated

These cells die b a rocess of a o tosis(programmedcelldeath).

Si n that a T cellmediated immune res onse

hadoccurredisthepoolofsurvivingmemorylymphocytes.



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n gen ecogn onan os mu a on

RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation


Responsesof TLymphocytestoAntigen&Constimulation

Secretionofcytokines&expressionofCytokinesreceptors Clonal Expansion



DeclineoftheImmuneResponse BiochemicalPathwaysofTcellActivation



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,

Tcells

express

proteins

that

are

involved

in

, ,

functionsofthecells



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Pr t in r c anti n tim lat T c ll



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S.Wahyuni/lecture/immunology/S1 506/14/2012


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proteinsinboththeAPCandTcellmembranesatthepointofcell:cell contact

Theseproteinsareinvolvedinadhesionand

signalingandareimportantforoptimalinductionofactivatingsignalsintheTcell.

RegionofcontactbetweentheAPCandTcell,

includingtheredistributedmembraneproteins,iscalledtheimmunologicsynapse.



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BindingofCD4/CD8(coreceptor)toMHCactivatesatyrosineprotein

kinase (Lck)

Bin ingo TCRtopepti a activatet etransmem rane signa ingo

CD3and chains.CD3and chainscontainimmunoreceptor

tyrosinebasedactivationmotifs(ITAMs)

ActivatedLck willphosphorylates tyrosineresiduesinITAMs



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ITAMsofthe chainbecomedockin sitesforatyrosinekinase calledZAP70(associatedproteinof

70kD),whichisalsophosphorylated byLck and.

TheactiveZAP70thenphosphorylates variousadapter

proteinsandenzymes,whichassembleneartheTCRcomplexandmediateadditionalsignalingevents.

Twomajorsignalingpathwayslinkedto chain :

calciumNFATpathway

Ras RacMAPkinase athwa .



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recognitionwithTcellresponsesconsistof:

recruitmentofadapterproteins


NuclearfactorofactivatedTcells(NFAT)


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ThecalciumNFAT athwa isinitiatedb ZAP70mediatedphosphorylation andactivationofanenzyme

calledphospholipase C(PLC),whichcatalyzesthe.

OnebyproductofPLCmediatedphospholipid

breakdown,calledinositol 1,4,5triphosphate(IP ),stimulatesreleaseofCa2+ ionsfromintracellularstores.

Atthesametime,signalsfromtheTCRcomplexleadto.



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C to lasmic Ca2+ bindsa roteincalledcalmodulin andtheCa2+calmodulin complexactivatesaphosphatase

calledcalcineurin.

senzymeremovesp osp a es roman nac vecytosolic transcriptionfactorcallednuclearfactorof

activatedTcells. Oncedephosphorylated,NFATisabletomigrateinto

thenucleus,whereitbindstoandactivatesthe,

encodingtheTcellgrowthfactorinterleukin2andcomponentsoftheIL2receptor



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inhibitstheactivityofcalcineurin andthus.

Thisagentiswidelyusedasan

rejection;itsadventhasbeenoneofthe

transplantationinthepastdecade



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dependentphosphorylation andaccumulation,

leadingtotherecruitmentofRas orRac and

guanosine diphosphate (GDP).



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BothRasGTPandRacGTPinitiatedifferentenzymecascades,leadingtotheactivationofdistinctMAP

kinases.

extracellularsignalregulatedkinase (ERK)andcJunamino(N)terminalkinase (JNK),promotethe

phosphorylation ofanotherproteincalledcJun.

CFos andphosphorylated cJuncombinetoformthe ,

whichenhancesthetranscriptionofseveralTcellgenes.



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mediatedhydrolysisofmembraneinositol

PLC1willactivatediacylglycerol (DAG)

DAGw act vateer net reon ne nase ca e

proteinkinase C(PKC)thenleadactivationof

t etranscr pt on actornuc ear actor B).



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inaninactiveform,boundtoaninhibitorcalledIB.

TCRsignalsgeneratedbyantigenrecognition

leadtophosphorylation anddissociationoftheboundinhibitorofNFB.Asaresult,NFB isreleasedandabletomovetothe

nuc eus,w ere tact vatest etranscr pt onoseveralgenes.



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immunity,thearmoftheadaptiveimmunes stemthatcombatsintracellularmicrobes

TheresponsesofTlymphocytesconsistof

se uential hases: reco nition of cellassociatedmicrobesbynaiveTcells,expansionofthe

antigenspecificclonesbyproliferation,and

differentiationofsomeoftheprogenyintoeffector cellsandmemorycells.



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Tcellsusetheiranti enrece torstoreco nize:

peptideantigensdisplayedbyMHCmoleculesonantigen

presentingcells(whichaccountsforthespecificityofthe

polymorphicresiduesoftheMHCmolecules(accountingfortheMHCrestrictionofTcellresponses).

AntigenrecognitionbytheTCRtriggerssignalsthataredeliveredtotheinteriorofthecellsbymoleculesassociated with the TCR the CD3 and chains and b

thecoreceptors,CD4orCD8,whichrecognizeclassIIorclassIMHCmolecules,respectively.



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Thebindin ofTcellstoanti en resentin cellsisenhancedby:adhesionmolecules,notablytheintegrins,whose

producedinresponsetomicrobes

antigenrecognitionbytheTCR.

APCsexpose tomicro esortocyto inesproducedaspartoftheinnateimmunereactionsto microbes ex ress costimulators that are

recognizedbyreceptorsonTcellsanddelivernecessary"secondsignals"forTcellactivation.



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Inres onsetoanti enreco nitionandcostimulation Tcellssecretecytokines,someofwhichinduce

proliferationoftheantigenstimulatedTcellsand.

CD4+ helperTcellsmaydifferentiateintosubsetsof

effector cells: TH1cells,whichproduceIFN,activatephagocytesto

eliminateingestedmicrobesandstimulatetheproduction .

TH2cells,whichproduceIL4andIL5,stimulateIgEproductionandactivateeosinophils,whichfunctionmainly

.



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CD8+Tcellsreco nize e tidesofintracellular(cytoplasmic)proteinantigensandmayrequire

helpfromCD4+Tcellstodifferentiateintoeffector.

cytoplasmic microbialantigens.

ThebiochemicalsignalstriggeredinTcellsbyantigenrecognitionresultintheactivationofvarioustranscriptionfactorsthatstimulatethe

,

receptors,andothermoleculesinvolvedinTcellresponses.


cell mediated immunityy

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