InteractionsofPhagocytesandOtherImmunologicalCellsBIOL533Lecture7MedicalMicrobiologyBIOL5331ProductionofAbandActivationofMacrophagesandCytotoxicTCellsT-DependentT-IndependentBIOL5332T-DependentActivationExtracellularpathogensDigestedbymacrophage—AgcomplexedMHCclassII(presentonlyinmacrophageandfewothercelltypes)StimulateshelperTcells(TH2)tofindBcells,recognizeparticularpeptidefragmentAbHelperTcells(CD4+cells;TH1)producesIFNandactivatesmacrophageBIOL5333T-DependentActivationIntracellularpathogensDigestedwhenreleasedfromdyinghostcellPeptideAgpresentedonMHCclassIProliferationofcytotoxicTcells(CD8+)BIOL5334ProcessingCHOandLipidAgLPSinteractsdirectlywithBcells(independentofTcells)CHOAglargelyindependentofTcells,butsomeinvolvement(productionofcytokines;necessaryformaximalBcellactivity)BIOL5335T-DependentMechanismMacrophagepresentspartofAgandownclassIIMHCtoT-helpercell(signal#1)AlsomakesIL16(signal#2)IL16stimulatesTcellclonetodivideandmakeIL24-6IL1alsostimulateshypothalamustoraisebodytemperature,enhancingTcellactionBIOL5336T-DependentMechanismIL24-6stimulateT-helpercellstomultiplyTheseTcellsassociatewithBcellsthathavecorrectAg—MHCIIcomplexandsecreteBcellgrowthfactors(BCGF)thatcauseBcellstomultiplyBIOL5337T-DependentMechanismThenumberofBcellsincrease,T-helpercellsproduceothercytokines(BCDF)ThesecausesomeBcellstostopdividing,differentiatingintoplasmacellsandproduceAbAlsoBcellrecognizesitsAgthroughitssurfaceIgMreceptor(signal#1forBcell),subsequentlytriggeredtoproliferateplasmacellsAbBIOL5338TCellBiologyMHCmoleculesMajorHistocompatibilityComplexFoundonplasmamembraneClassIfoundonmostnucleatedbodycellsClassIIfoundonlyonleukocytesinvolvedinimmuneresponse(macrophage,Ag-presentingcells,Bcells)ClassIandIIAgprocesseddifferentlyBIOL5339TCellBiologyClassImoleculesbindtopeptidesfoundincytosol(e.g.,replicatingviruses)EndogenousproteinsaredigestedbynaturalprocessesPeptidesfromcytosolendoplasmicreticulumBIOL53310TCellBiologyWithinER,classIMHCheavychainsynthesizedandassociateswith2microglobulinDimerbindspeptideplasmamembraneIfpeptideisforeign,passingCD8+Tcell(cytotoxic)recognizes,releasescytokines,destroyscellBIOL53311TCellBiologyClassIIMHCbindtofragmentsarisefromexogenousAgPeptiderecognizedbyCD4+T-helpercellsDonotdirectlykillcellcellsenlargeanddividemoreCD4+cellsSecretecytokines(suchasIL2)eitherdirectlyinhibitpathogenorrecruitothercellsforimmuneresponseBIOL53312MHCGeneticsMHCgenecomplexlocatedchromosome6ABCDco-dominantIndividualsmayhaveanycombinationof8differentMHCmoleculesOnegeneofeachpaircodeforMHCBIOL53313MHCGeneticsTypesofGenesClassI ABCClassII DClassIIIEncodesecondcomponentofcomplement(C2)—classicalpathwayFactorB—alternatepathwayTwoforms;4thcomplementcomponents(C4aC4b)BIOL53314RegulatorTCellsT-helperCD4+TH1:IL2,IFN,TNF;macrophageactivationTH2:IL4,5,10,13;humoralimmunityTH0:notmuchknownT-suppressorBIOL53315RegulatorTCellsT-helper:twosignalsforstimulationbyAgAgfragmentspresentedtoTcellbymacrophage,dendritic,oractivatedBcell+MHCclassII;neededforrecognitionbyT-cellreceptorandCD4proteinonsurfaceTH1cellCD28proteinreceptoronTH1cellsCD28bindstoCD80onmacrophage2ndsignal;bothgointocytoplasmofTH1cellBIOL53316RegulatorTCellsSignal1activatestyrosinekinaseAddsphosphategroupstotyrosineinproteinsEnzymephospholipaseCIcleavesphosphatidylinositolbisphosphateinTcellhelpermembraneTwocleavageproducts;twopathwaysFirstdiacylglycerolactivatesproteinkinaseCProteinkinaseCmovesintonucleuscatalyzesformationproteincomplexAP1BIOL53317RegulatorTCellsSecond,inositoltriphosphatecausesCachanneltoopen;Ca++ionsrushincytosol;activationofcalmodulin,calcineurin,andnuclearfactorofactivatedTH1BIOL53318RegulatorTCellsNF-ATnucleoplasmbindstoAP-1 NF-AT/AP-1(transcriptionfactor)TranscriptionfactorbindstoDNAspecificgenesequence:IL2m-RNAtranscribedIL2m-RNAribosomeswhereIL2proteinproducedBIOL53319RegulatorTCellsSignal2mediatedCD28receptorplusCD80moleculeactivatesanothertyrosinekinaseformationtranscriptionfactorCD28RC;alsostabilizesIL2m-RNA;increasesconcentrationofIL2TH1cellsactivatedby2signalssecretelargeamountsofIL2activatescytotoxicTcellsBIOL53320RegulatorTCellsSignal2mediated,cont’d.AlsosecreteIFNwhichactivatesmacrophagesandenhancesantimicrobialactivityTH2cellscostimulatedbyAgpresentationandIL1,thenreleaseseveralcytokinesthatstimulateBcellproliferationanddifferentiationintoAbformingplasmacellsBIOL53321CytotoxicTCellsCD8+DestroytargetcellsCD95pathway(fasgeneproduces;apoptosissequence)Perforinpathwaydirectcytolysis;secretionofperforinandgranzymeproteinsBIOL53322CytotoxicTCellsCD8+CD95PathwayCD95transmembranefasprotein