TcellActivation-2(16part2).DrMohammadEmad.

Doneby:RaghadShweikiandLubnaAlnatour.

TCellsRecognizeOnlyPeptides

• Tcellsonlyrecognizeantigensthatarepolypeptides (in the majority of conditions) andonlywhenthosearepresentedonMHCproteins.• TherestrictionofCD4cellsandCD8cellstobindMHC-IIorMHC-IisduetothefactthatbindingsitesontheTCRonlyrecognizetheappropriateMHCprotein(CD4canonlybindMHC-II,andCD4willstabilizethatconnection,whereasaCD8cellscandosobutonlywithMHC-I)• Furthermore,theCD8andCD4proteinswhichstabilizetheconnection,furtheraidinthisrestriction.

• MHC-Iareusuallyusedtopresentintracellularlyproducedantigens(viralproteinsforexample)because we want cytotoxic T cells to be the dominant factor here (cellular immunity) MHC1 usually only shows what is inside the cell ,MHC-IIproteinsusuallypresentantigensofextracellularorigin (bacterialproteins)MHC2iswiththeregulatorypartoftheadaptiveimmunity - twodistinctpathwayswithdistinctorganellesusedforeach.

• ThisiswhywhenIgiveavaccinecomposedofdeadviralcells,itwillnotcauseaCD8(cytotoxicresponse) andcauseanantibodyresponseAstheseviruseswillnot bepresentedonMHC-Icells,becausetheydidnotreplicateandinfectcells.

• TheywillinsteadbepresentedonMHC-IIandgothroughtheBcellhumoralresponse.That’swhythemajorityofvaccineswillbecomeextracellularantigenswhicharetakenupbyAPSwhichpresentedtocd4cellsandthenproduceath2 orhumoralresponse.

• Youwillhavereadymadeantibodiesthatwilltrapthevirusbeforeentrytocells(orwhentheyburstopencells)that’sthemajorityofyourdefensethatyougetfromthevaccinewhichisactuallyprotective-sonexttimeyoumeetthevirus,youhaveantibodiestointerceptbeforeitentersyourcells-.

• Thisrestriction,isduetothedistinctionintheacquisitionandPROCESSING oftheseproteins(betweenintracellularpartsandextracellularparts)throughdifferentorganellesandpathways.

• 1)Anendogenousprotein(viralprotein– cancerprotein)isprocessedindifferentcompartments(thatwillultimatelyrestrictthemandmarkthemasintracellularproteinswithinthecytoplasmandthentheyaredifferentincompartmentthanthosederivedfromextracellularsources).

• TheassociationofendogenousforeignproteinswithMHC-Icomplexhappensduethisdifferenceinprocessing,wheretheseproteinsarecleavedbyaproteasomeintosmallerpartsandthenthepeptidesarechaperonedbya“TAPtransporter”thattransportstheseproteinstotheRoughERwhereitislinkedwithMHC-I.thisprocessiscompletelydistinctandseparatedfromtheotherprocessifproteinisderivedfromextracellularsources.

• Theendogenousprotein-MHC-IcomplexnowtravelstoGolgi(likemakinganyinternalprotein)andthentothecellsurfacewhereitispresentedà inshort,MHC-IpresentedproteinsgothroughthetypicalendogenousproteinmanufacturingprocessandenduponMHC-I

• 2)Theotherrouteisforextracellularproteins (thiswillbetakenbyPhagocytes)isthroughthecleavageoftheseproteinsinanendosome(asopposedtoroughER),thisiswherethepeptidefragmentsarelinkedwiththeMHC-IIproteinintoacomplex.

• Fromtheendosome thepeptide-MHC-IIcomplexmigratestothecellsurface.• Majorquestion:whydon’ttheintracellularproteins–someofthosegetdegraded,getpresentedonMHC-II?àThereisaprotectionmechanismplacedherethat(mostly)preventsendogenouslyproducedproteinsfrombeinglinkedwithanMHC-IIprotein (andhencetherestrictionmechanismwouldbebypassed).

• ThisoccursduetothepresenceofaninvariantchainattachedtoMHC-IIproteinswhentheyarenotinsidetheendosome (sortoflikealockmechanism),noproteinswillbeabletoattachtoMHC-IIoutsidetheendosome (whileitisbeingsentfromendosome tothemembranebecauseMHC2proteinsarebeingproducedsomewhereelse(golgi)fromindigenousproteins),andnoendogenouslyproducedproteinsentertheendosome,effectivelycreatingtherestrictionmechanism.(thelockmechanismisonlyremovedforMHC-IIproteinswithintheendosomeonly).

• ThatisthemainprotectionmechanismofhowIpreventintracellularproteinsfrombindingmyMHC2complex,becauseifIpresentingMHC2withindigenousproteinstocd4cellsthentheywillbecomeactivateagainstmyindigenous(self)protein(iftheydon’tmeetthisproteininthymusduringtrainingbymistake)soIwillhaveautoimmunedisease.

Importantinformation

• What as you are breaking down a protein How is the most unique part of the protein selected?... Actually they don’t know.. What happens is that the protein is not just a sequence of amino acids, it is actually folded in the secondary and tertiary structures and every protein is unique otherwise all protein have the same function, so when I break this protein down I will find that my enzymes find it hard to reach the areas of protein that are heavily folded, so when it cuts the protein these remaining parts that my enzymes could not get into will be the most unique part of the protein and that is usually presented to the MHC molecules

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026165/figure/F2/

*some crossing between the two pathways DOES occur:MHC-I can bind peptides derived from exogenous proteins internalized by endocytosis or phagocytosis then exit it by certain mechanisms , a phenomenon called cross-presentation. which is good actually because i might want to see if this cell is infected by something that is not being picked up..this is a protection mechanism.

this i Specific subsets of dendritic cells (DCs) are particularly adept at mediating this process, which is critically important for the initiation of a primary response by naïve CD8+ T cells

This is actually beneficial which would allow cytotoxic response against certain cells that have taken up certain toxic material (toxins)

Extracellularprotein

• AsforBcellsthestoryisquitedifferent,thesecellsinteractwiththeirsurfaceimmunogloblulin(IgMandIgD)(notaTCR).

• SinceantigenpresentationwithMHC-IIisnotneededtoactivateBcells(notalways).RemembertheTcellindependentantigenloopandtheabilityofBcellstopresentantigens(whicharenotalwayspeptides),whichultimatelyactivatethemselvesindirectlybypresentingtheantigentoaCD4cell.• IncontrasttoMHC-IIantigenpresentation,whereitcanonlypresentpeptides,theIgMandIgDantigenreceptorsonthesurfaceoftheBcellcanrecognizenonpeptides asantigens(polysaccharides,nucleicacids,andsmallmolecules-drugssuchaspenicillin-).

• Asmentionedinpreviouslectures,thisishowhaptens (nonpeptidesandsmall)canbypassthepeptiderequirement(byconjugatingthemtocarrierprotein)andactasanimmunogen (andthensatisfythesizerequirementusingthecarrierprotein).

• ThentobeassociatedwithMHC-IIantigenpresentation,thecarrierprotein’speptidesareinsteadusedinthiscase,bypassingathirdrequirement(peptidepresentingtoCD4onMHC-II)toactivateCD4helperTcellsthenIwillhaveaTcelldependentBcellactivationandthenlcanclassswitchmyantibodiesandmakeIgg orsomethingelse.

• NowatthispointthehelperTcellwillproducetheappropriatecytokines(lymphokines)toactivateatheBcelltostartproducingantibodiesagainstthishapten complex

• Signaltransduction:• Antigen-MHCcomplexontheAPCinteractswiththeTCRonthesurface,theeffectothisinteractionisproducedbyasignalsentfromtheTCRtotheinsideofthecell(nucleus).• ThesignalistransmittedbytheCD3proteinwhichdetectsifthetcell receptorisoccupiedandthenittransmitthesignaldowntothenucleus (rememberCD3isapartoftheTCR)complexthroughcertainpathwaysthateventuallyleadtoaninfluxofCalciumintothecell(thestimulustotransducethesignal).• TheinfluxofCalciumcauses(activates)aspecificprotein(Calcineurin)(aserinephosphataseenzyme)toexertitsenzymaticfunctioninthenucleus(switchonthegenesforIL-2andIL-2receptor)• Nowthatweknowwhatiscalcineurin andhowitfunctions,wecanremoveMHC-IIcellmediatedimmunitybyblockingcalcineurin(adrugcalledcyclosporinedoesthis),thisisusefulinorgantransplantation(cellimmunityisresponsiblefororganrejection*)andautoimmunediseases.• àbutwhydoesblockonlycellmediatedandnotABmediated?BecauseyouhaveblockedIL-2whichyouwillneedforthemaintenanceofath-1 response.

IL-2

• IL-2isproducedbyCD4cellswhichisactivatedbyAPCpresentingonMHC-II

• IL-4fromunknownsourceiswhatactivatesTh2response!

• SignaltransductionpathwaysinvolvedinT-cellanergy.• StimulatorysignalsdeliveredbytheengagementoftheT-cell

receptor(TCR;signal1)andco-stimulatorymolecules(CD28;signal2),bothworktoinducedifferentsignalingpathwaysthatresultintheactivationofmultipletranscriptionfactorsatthegenelevel

• Thepositivesignalsinclude:• 1- phospholipaseC1(PLC1),whichinducestheCa2+influx, which

thenactswithcalmodulinandcalcineurin.• 2- nuclearfactorofactivatedTcells(NFAT)- nuclearfactor-B(NF-

B)pathway byPKC• 3- proteinkinaseC(PKC),whichregulatethenuclear4- activator

protein1(AP1)pathways.(controlledbysignal2-costimulation)• Inthenucleus,NFAT+AP1+othertranscriptionfactors=inducea

programofgeneexpressionthatleadstointerleukin-2(IL-2)productionandactivation.

• TCRengagementintheabsenceofco-stimulation(signal1withoutsignal2)resultsintheinductionofNFATproteinswithoutconcomitantAP1activation(youwillnotactivatePKC). IntheabsenceofcooperativebindingtoAP1,NFATalonewillregulatethetranscriptionofadistinctsetofgenesthatwillproduceanergyresponseNOIL-2,suchasCasitasB-lineagelymphomaB(CBL-B).Anergy-associatedfactorsinhibitT-cellfunctionatdifferentlevelsleadingtoT-cellunresponsiveness(NOIL-2PRODUCTION).

1

2

3

signal1

signal2

UltimatethingsIwanttoactivatethegenesontheIL-2locus

• Itisinthisstep(IL-2production)thatclonalproliferationofhelperTcellshappensforthatspecificantigen(youwillalwayshavememoryagainstthisantigen)- meaningiftheCD4cellreachestheIL-2productionlevel, itwillalsoproliferatetomakeclonesforitself:• IL-2(alsoknownasT-cellgrowthfactor),stimulatesthehelperTcelltomultiplyintoacloneofantigen-specifichelperTcells(italsostimulatesCD8cells).• ThemajorityofthesehelperTcellswillcarryouttheireffectorandregulatoryfunctions.• FromtheseclonesofcellsafewarekeptawayasmemoryCells forrapidfunctioninsubsequentexposurestothisantigen.• CytotoxicTcellsandBcellsclonesmadeforaspecificantigenalsoformmemorycells.• ActivatedCD4-positiveTcellsalsoproduceanotherlymphokinecalledgammainterferon,whichenhancestheabilityofAPCsbymakingthemproducemoreMHC-IIproteins(andthuspresentmoreantigen).• Gammainterferonalsoenhancesthemicrobiocidalactivityofmacrophages.

• ItisimportanttoknowthatactivationofTcellsisnotallornone.Thereisagreyareaofpartialactivationthatmayoccur.• Fullactivationhasthefullcomplementoflymphokinesreleased,partialactivationleadstoareleaseofafewofthoselymphokineswhich wouldleadtoaweakerresponse.• ThisisdependentontheepitopethatwasusedintheactivationoftheTcell,whichwouldresultinadifferenttransductionpathwaysbeingusedfortransductionofthesignal(andactivationoftheproperlymphokineproducinggenes)• Theexplanationforthisisasfollow(whichexplainswhysomepeoplecanclearcertaininfectionsmoreefficientlythanothers…genetics!Perhapsevenrandomevents)• AsourcellshavethreegenesfortheclassIlocus(A,B,andC)andthreegenesattheclassIIlocus(DP,DQ,andDR)fromeachparent(foratotalofsixpossiblecopiesofeachgeneinClassIor6copiesmakingClassIIproteins).• aseachgenecopyhasmultipleallelesforeachlocus,eachMHCproteinisnowabletopresentpeptideswithdifferentaminoacidsequence

MemoryTCells• Withthesecellsweareabletomountaquicker,effectiveresponsetoantigens–YEARS– aftertheinitialexposuretoanantigen.

• Thismemoryresponsetoaspecificantigenisduetoseveralfeatures:• (1)inthefirstexposuretoanantigen,thereareveryfewcellsrespondingtothisstimulus(theyhavetostartfromzerocells),foractivationofCD4cellsandsoon,secondexposurewillfindmanycellsalreadyproducedandready(don’tneedtostartfromzeroatthispoint)(so each time you meet the same antigen, your memory gets stronger and stronger because you need to have a larger response for it rather than an antigen you’d only get exposed to it once -> Low memory for this antigen).

• SoaTcellhastoreachactivation(productionofIL-2)byfindingproperMHC-IIandTCRinteraction,thenreachactivation,atthispointsomeofthecellsarekeptasmemorycells.

• (2)cells(asopposedtoantibodies)canliveformanyyearsandreplicatethemselves(maintenance)whereasantibodies cannot(they’d survive for months at best).

• (3)amemorycellhasaspecialabilitywhichallowsittohaveamuchstronger(almostexaggerated)responsetoasmalleramountofantigen,andwouldrequirelesscostimulation,thisheightenedresponseisbecausethesecellsproducehigheramountofinterleukinsthanregularnaïvecells,thisisthebasishowyourmemorycellswillproduceafastresponseagainstacertainantigen.

TheT-CellReceptor• Fromtheprevious/nextfigurewefindthatthetheTCRiscomposedofcomposedof2polypeptidechains(alphaandbeta),whichareassociatedwithCD3proteins(theTcellreceptorandCD3proteinworktogetherinreceivingtheantigen- mostlyTCRandtransductionofthesignal,whichisdonemainlybyCD3alongsideTCRtransmembraneapparatus).

• InorderfortheTCRtodetectmanydifferentantigens,itthushasastructurethatresemblesimmunoglobulinheavychainsinafewwayswhichwouldallowittobindtodifferentantigens:

• (1)thegenesthatcodeforTCRchainsaremadebytherearrangementofmultipleregionsofDNA(whichcreatesvariability)

• (2)thegenelocihavemanysegments-V(variable),D(diversity),J(joiningVandDwithC),andC(constant),allofwhichworktogethertoprovidehighvariabilityanddiversity(atthislevelofdiversitymorethana100milliondifferentreceptorproteinscanbemade)

• (3)thevariableregionshavehypervariabledomains (evenmorediversityattheendoftheprotein)• (4)thetwogenes(RAG-1andRAG-2)thatencodetherecombinaseenzymesthatcatalyzethesegenerearrangementsaresimilarinTcellsandBcells.

Why do we have to have a constant region? Because we want to have a constant reaction with the TCR.Antibodies have the same thing, every antibody should have FC region recognized as a constant region by phagocytes for example.

• variable(V),diversity(D),joining(J)genesegments,andconstant(C)genes.• TheTCRαlocus(chromosome14)consistsof70–80Vα genesegments,eachprecededbyanexonencodingtheleadersequence(L)inwhite.Aclusterof61Jα genesegmentsislocatedaconsiderabledistancefromtheVα genesegments.TheJα genesegmentsarefollowedbyasingleCgene,whichcontainsseparateexonsfortheconstantandhingedomainsandasingleexonencodingthetransmembraneandcytoplasmicregions.TheTCRβlocus(chromosome7)hasadifferentorganization,withaclusterof52functionalVβ genesegmentslocateddistantlyfromtwoseparateclusterseachcontainingasingleDgenesegment,togetherwithsixorsevenJgenesegments andasingleCgene.EachTCRβCgenehasseparateexonsencodingtheconstantdomain,thehinge,thetransmembraneregion,andthecytoplasmicregion(notshown).TheTCRαlocusisinterruptedbetweentheJandVgenesegments byanotherT-cellreceptor locus—theTCRδ locus

https://www.ncbi.nlm.nih.gov/books/NBK27145/bin/CH4F11.jpg

https://images.nature.com/full/nature-assets/gene/journal/v17/n3/images/gene20169f1.jpg

https://www.ncbi.nlm.nih.gov/books/NBK27145/bin/CH4F12.jpg

• Fromthepreviousfigures,wecandeducethateachTcellhasauniqueTCRonitssurface,withhundredsofmillionofdifferentTcells(withdifferentspecificreceptors)ineachhumanbeing.

• EachuniqueTcell,onceactivated,willproliferate(clonalexpansion),toyieldalargenumberofcellsthatareabletodealwiththespecificantigentheyareuniqueto.

• Antibodieshaveasimilargeneticrearrangementthatyieldsahighnumberofhypervariable antibodies.

• However,theTCR(eventhoughitisuniquelyspecifictoanantigenlikeanantibodyis),itdiffersfromtheantibodyintwoways:

• (1)ithastwochainsratherthanfour(2)itrecognizesantigenonlyinconjunctionwithMHCproteins,whereasimmunoglobulinsrecognizefreeantigens.

• ThisiswheretheBcell(Tcellindependentactivation)isappreciated,Bcellsdon’tuseTCRbutuseanimmunoglobulin(IgMorIgD)sotheybypasstheneedofMHC.

• AlsoTCRproteinsarealwaysanchoredintotheoutermembraneofTcells,Thereisnocirculatingformasthereiswithcertainantibodies(monomericIgMisintheBcellmembrane,butpentamericIgMcirculatesintheplasma)Note:- Antibodiesarecomposedof4chains(heavyandlight)whileTCRsarecomposedof2chains(alphaandbeta).- IgMAbarehuge,that’swhytheycantcrosstheplacentawhileIgGaresmallerandcan crosstheplacenta.

EffectofSuperantigensonTCells• Certainproteins,particularlystaphylococcalenterotoxinsandtoxicshocksyndrometoxin(TSST),actas“superantigens”(nextfigure).• Incontrasttothetypicalantigen,whichactivatesone(orafew)helperTcell,superantigensare“super”becausetheyactivatealargenumberofhelperTcells.• Forexample,toxicshocksyndrometoxinbindsdirectly toclassIIMHCproteinswithoutinternalprocessingofthetoxin.Thiscomplexinteractswiththevariable

portionofthebetachain(Vβ)oftheTCRofmanydifferentTcells.MEANINGTHESEANTIGENSHAVEREGIONSTHATAREDETECTABLEBYMANYDIFFERENTTCRs(overcomestheirspecificity)- whichwillproduceaheightenedexaggeratedresponse.• ThisactivatestheTcells,causingthereleaseofIL-2fromtheTcellsandIL-1andtumornecrosisfactor(TNF)frommacrophages.Theseinterleukinsaccountformanyofthefindingsseenintoxin-mediatedstaphylococcaldiseases.• Certainviralproteins(e.g.,thoseofmousemammarytumorvirus[aretrovirus])alsopossesssuperantigen activity

Top:the“regular”antigenprocessingbyanAPCisshown,theepitopeisthenpresentedontheMHC-IIcomplexandsignaltransductionandactivationoffewhelperTcellensues.

Bottom:thesuper-antigen,isDIRECTLYWITHOUTPROCESSING(soitisFASTacting)isboundtoMHC-IIproteincomplex(usingtheVβportionoftheTcellreceptor).

Becauseitbypassestheantigen-specificsite,super-antigen canactivatemanyhelperTcells.

FeaturesofTCells

• Tcellsmakeupabout65%to80%oftherecirculatingpoolofsmalllymphocytes,therestareBcells.• Withinlymphnodes,Tcellsarefoundintheinnerandsubcorticalregions,whereasBcellsarelocatedprimarilyinthegerminalcentersofthelymphnode.• Tcellshaveaverylonghalflife,theycansurviveformonthsorevenyears.• Thesecellscanbestimulatedtoproliferatebyusingmitogens(mitosisgeneratingmolecules).• mitogensforTcellsinclude:phytohemagglutinin orconcanavalin A[endotoxin,alipopolysaccharidefoundonthesurfaceofgram-negativebacteria,isamitogenforBcellsbutnotTcells]).• Tcellsaredetectedinbloodbyusingsheepblood,thisisbecauseallTcellshavereceptorsontheirsurfacethatreactswithsheepRBCs,andformauniquestructureseenbytheeye“rosettes”.

https://www.google.jo/imgres?imgurl=http%3A%2F%2Fwww.pathguy.com%2Fsol%2F16282.jpg&imgrefurl=http%3A%2F%2Fwww.pathguy.com%2Flectures%2Fwbc12.htm&docid=qu8FtQMYH3myOM&tbnid=_FAVF_4qioec6M%3A&vet=10ahUKEwjLx764xtbWAhVJnRoKHR0-DisQMwglKAAwAA..i&w=1000&h=661&bih=754&biw=628&q=t%20cell%20rosette&ved=0ahUKEwjLx764xtbWAhVJnRoKHR0-DisQMwglKAAwAA&iact=mrc&uact=8

EffectorFunctionsofTCells- recap

• ThefourtypesofTcells(Th-1,Th-2,andTh-17typesofCD4cells,andCD8cells)mediatedifferentaspectsofourhostdefenses.• Th-1cellsmediatedelayedhypersensitivityreactionsagainstintracellularorganisms.• Th-2cellsmediateprotectionagainsthelminths(worms)–antibodyresponse- .• Th-17cellsprotectagainstthespreadofbacterialinfectionsbyrecruitingneutrophilstothesiteofinfection.• CD8cellsprotectagainstviralinfectionbykillingvirus-infectedcells.

Th-1Cells• Th-1cellsandmacrophagesarethemaineffectorsofcellmediated(alsocalleddelayedhypersensitivityreactions,typeIVhypersensitivityreaction).

• Thistypeofreactionisaimedtoprotectagainstintracellularpathogens(fungiHistoplasmaandCoccidioides)and(bacteriasuchasM.Tuberculosis),themainsignalingmoleculeinthistypeofreactionisGAMMAINTERFERON,withothersignalsthathelprecruitorexcludemacrophages(macrophageactivationfactorandmacrophagemigrationinhibitionfactor(MIF))alsoplayarole.

• Theactualfunctionofdestroyingtheseintracellularpathogensisperformedbymacrophages,howeverTh-1cellsdirectmacrophages(recruitthemtothesiteandtellthemwhattolookfor)bytheproductionofinterleukins.

• Ifonehasadiminisheddelayedhyprsensitivity reaction,theywillofcoursebeunabletoclearthesepathogens.

• ThewellstudiedcaseofM.tuberculosis,aspecificlipoproteinofthebacteriumispickedupandthenstimulatesaspecificToll-likereceptoronthemacrophage,whichsignalsthecelltosynthesizeIL-12(indicatingthataforeignobjectwasencountered).• IL-12isaninducerofthecorrecttypeofresponsetothislipoprotein (cellularTh1response),thusIL-12inducesnaïvehelperTcellstodifferentiateintotheTh-1typeofhelperCD4Tcellstostartthedelayedhypersensitivityresponse,atthispointTh-1cellsproducegammainterferon,whichactivatesmacrophages,therebyenhancingtheirabilitytokillM.tuberculosis.• ThisIL-12–gammainterferonaxisisveryimportantintheabilityofourhostdefensestocontrolinfectionsbyintracellularpathogens,suchasM.tuberculosis andListeriamonocytogenes.• recap:Macrophagefoundaforeignproteinà IL-12à activateTh1CD4cellsàG-INFàactivatemacrophages

http://jcytol.org/articles/2015/32/3/images/JCytol_2015_32_3_188_168855_f1.jpg

https%3A%2F%2Fes.pinterest.com%2Fpin%2F511791945128312722%2F&psig=AOvVaw2m865HFKRWZCyzcncJuLhx&ust=1507713543060028 http://www.vet.cornell.edu/news/Images/tuberculosisbacteria.jpg

Histoplasmosis coccidosis TB

Acidfaststainhere.

Th-2Cells

• Th-2CD4cellsalongwitheosinophils constitutethemaineffectorsofreactionsthatareprotectiveagainsthelminths (worms)suchasSchistosomaandStrongyloides (rememberIgE andeosinophils).

• ThemostimportantinterleukinsforthesereactionsareIL-4 (why?BecauseweneedTh2responsetoproduceIL-4),

• IL-4increasestheproductionofIgE,andIL-5,whichactivateseosinophils.• IgE bindstothesurfaceoftheworm.EosinophilsthenbindtotheheavychainofIgEandsecretetheirenzymesthatdestroytheworm.

• Th-17Cells• Th-17cellsprotectagainstthespreadofbacterialinfectionsatmucosalsurfacesbyproducingIL-17.àIL-17attractsneutrophilstothesiteofinfectionwhereuponthebacteriaareingestedanddestroyed.

CD8Cells

• CD8cellsmediatethecytotoxicresponsethatisconcernedprimarilywithdestroyingvirus-infectedcellsandtumorcellsbutalsoplayanimportantroleingraftrejection(MHC-I).• Inresponsetovirus-infectedcells,theCD8lymphocytesmustrecognizebothviralantigensandclassImoleculesonthesurfaceofinfectedcells.• Tokillthevirus-infectedcell,thecytotoxicTcellmustbeactivatedbyIL-2producedbyahelper(CD4-positive)Tcell,whereasaNKcelldoesn’t.• TobecomeactivatedtoproduceIL-2,helperTcellsrecognizeviralantigensboundtoclassIImoleculesonanAPC(e.g.,adendriticcellormacrophage).• TheactivatedhelperTcell,onceithasrecognizedtheMHC-IIwithviralepitope,willsecreteIL-2thatwillstimulatetheCD8cellthatisspecifictothatvirus- whichthenwillformacloneofthatnowactivatedcytotoxicTcells.

• ActivatedcytotoxicTcellskillvirus-infectedcellsprimarilybyinsertingperforins anddegradativeenzymescalledgranzymes intotheinfectedcell.• 1-Perforinsformachannelthroughthemembrane,thecellcontentsarelost,andthecelldies.• 2-Granzymesareproteases(enzymesthatdegradeproteins)andworkagainsttheproteinsinthecellmembrane,whichalsoleadstothelossofcellcontents.• 3-Granzymesalsoactivatecaspases(atypeofprotease)thatinitiateapoptosis,resultingincelldeath.• Afterkillingthevirus-infectedcell,thecytotoxicTcellitselfisnotdamagedandcancontinuetokillothercellsinfectedwiththesamevirus.• CytotoxicTcellshavenoeffectonfreevirus,onlyonvirus-infectedcells.

• ThemainApoptoticmechanism,bywhichcytotoxicTcellskilltargetcellsisactivationofapoptosisthroughthetheFas-Fasligand(FasL)interaction.• ThisapoptosismechanismhappenswhenFas (whichisaproteindisplayedonthesurfaceofmanycells)andcytotoxicTCRrecognizesanepitopeonthesurfaceofatargetcell(MHC-I),FasL(FasLigand)isinducedinthecytotoxicTcell.• OnceFasL andFas interact,apoptosis(death)ofthetargetcelloccurs.• NKcellscanalsokilltargetcellsbyFas-FasL–inducedapoptosis.

• Toeliminatevirusinfectedcell,anantibodymediatedmechanismisemployedaswell(InadditiontodirectkillingbycytotoxicTcells)thisisdonebyacombinationofIgGandphagocyticcells.

• Inthisantibody-dependentcellularcytotoxicity(ADCC),theantibodydirectedatthevirus,isboundtothesurfaceoftheinfectedcell.TheboundAntibodyisthenrecognizedbyphagocyticcells(macrophagesorNKcells)byanIgGreceptorontheirsurfaceà theinfectedcelliskilled.

• TheADCCprocessisthemechanismofkillinghelminths(worms).• However,inthiscase,ADCCismediatedbyIgE,andeosinophils(notphagocytes)aretheeffector(doesthefunction,inthiscasekilling)cells.

• Themechanismisquitesimilar,IgEbindstosurfaceproteinsontheworm,andeosinophilshaveareceptorontheirsurfacefortheepsilonheavychain(IgE).

• TheactualkillingismediatedbygranulesinsidetheeosinophilsthatarereleasedaftertheyareactivatedbyIgE,themajorbasicproteininthesegranulesdamagesthesurfaceoftheworm.

Herewehaveabridgebetweenhumoralandcellularimmunity.(enhancedphagocytosis).

So,cellularcytotoxicitycanbedirectedagainstnon-polypeptides(hereI’musingantibodieswhichcantargetantigensandpathogensthatarenotpeptides).

• Intumors,newantigens(notself)willbedisplayedontheirMHC-Isurfaceproteinà CD8cellswillrecognizethis(andwillstimulatedtoproliferatebyIL-2)andtargetthesetumorcellsfordestruction(eitherdirectorbyinducingapoptosis)

• IL-2producedmeansthatthiscloneofCD8cellwillproliferate,whichwillmeanthatthisCD8clonalexpansionisnowabletokillthistypeoftumorcells(thisphenomenoniscalledimmunesurveillance).

• Inallografts,cytotoxic(CD8)cellsrecognizetheclassIMHCmoleculesonthesurfaceoftheforeigncells(anddependingonhowsimilaritistotheself,theywilleitherrejectoraccept).

• ButwhatactivatestheseCD8cellsintheallograftrejection?TheyneedIL-2,producedbyhelper(CD4),theywillrecognizetheforeignclassIImoleculesoncertaincellsinthegraft(APCsfromtheallograft,macrophagesandlymphocytes).

• TheactivatedhelpercellssecreteIL-2,whichstimulatesthecytotoxiccelltoformacloneofcellsthatwillfunctiontokilltheallograftcells(thismeansnowthebodyhasmemoryagainstthisallograftandthereisverylittlethatwecandotohelp,thisalsomeansthatifweaimtoreduceallograftrejectionwemustworkonhavingtheCD4cellsnotactivatingclonesofCD8cellsthattargetthegraft.

Doesthismakeyouimmunetothistypeofcancer?Yesandno.Becauseyou’reimmunetothisstageofcancer.However,ifthecancerprogressesfurtherinothercellsthenanewreactionneedstobeproducedandcancercellsmayprogressfurtherinawaytheydon’tdisplayanythingORtheycancauseanergy.

GoodLuck!💚💚