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CellMediated
Immune
Responses
Sitti Wahyuni,MD,PhD
DepartmentofParasitology,
MedicalFaculty,Hasanuddin University
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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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PhasesofTCellResponses
u RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation
Ro eo Costimu ation inTCe Activation
Responsesof TLymphocytestoAntigen&Constimulation Secretionofcytokines&expressionofCytokinesreceptors Clonal Expansion
DifferentiationofNaiveTCellsintoEffector Cells
DevelopmentofMemoryTLymphocytes
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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PhasesofTCellResponses
n gen ecogn onan os mu a on
RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation
Ro eo Costimu ation inTCe Activation
Responsesof TLymphocytestoAntigen&Constimulation
Secretionofcytokines&expressionofCytokinesreceptors Clonal Expansion
DifferentiationofNaiveTCellsintoEffector Cells
DevelopmentofMemoryTLymphocytes
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.
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Th l l i l d i h ff
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Themoleculesinvolvedintheeffector+
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Th f ti f T 1 d T 2 b t f CD4+
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ThefunctionsofTH1andTH2subsetsofCD4+
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diff b T 1 d T 2 b f
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differencesbetweenTH1andTH2subsetsof
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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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PhasesofTCellResponses
n gen ecogn onan os mu a on
RecognitionofMHCAssociatedPeptides RoleofAdhesionMoleculesinTCellActivation
Ro eo Costimu ation inTCe Activation
Responsesof TLymphocytestoAntigen&Constimulation
Secretionofcytokines&expressionofCytokinesreceptors Clonal Expansion
DifferentiationofNaiveTCellsintoEffector Cells
DevelopmentofMemoryTLymphocytes
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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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
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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.
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