Medical Microbiology

ipherywillcontinuouslybeinducedtoundergoactivationandexhaustion

withinthesecondarylymphoidorgans.

ExhaustiveT-cellinductionmostlikelyoccursinresponsestohepatitisCvirus

andHIV,andhasbeenobservedinmiceexperimentallyinfectedwiththe

noncytopathicviruscausinglymphocyticchoriomeningitis.Successfulestab-

lishmentoflymphocytechimerismfollowinglivertransplantsappearsto

basedonthesameprinciple.Forexample,arelativelyshortperiodofimmu-

nosuppressionfollowingtransplantationmayallowtheestablishmentofnu-

merousdendriticcellsfromthetransplantedorganwithinthesecondary

lymphoidorgansoftherecipient,resultinginthesubsequentelimination

ofthoserecipientTcellswhichreactagainsttheforeignMHCmolecules.

TwoImportantExperimentsaddressingtheinductionof

ImmuneResponses

APCstransportantigenstotheperipherallymphoidorgansviathelymph

vessels.Skinflapexperiment.Toprovethatantigenscontactedatperipheralloca-

lizations(e.g.theskin)mustfirstbetransportedonAPCsthroughthelymphvessels

intothelocallymphnode,inordertoinduceanimmuneresponse—anexperiment

wasperformedinwhichaguineapigskinflapwaspreparedsuchthatthesupply

vessels(lymphvessel,veinandartery)remainedintactandfunctional.

Followingsensitizationoftheskinflapwithacontactantigentheanimalreactedto

asecondantigenicexposureoftheremaining(intact)skinwithacceleratedkinetics.

Whenthelymphvesselleadingfromthepreparedskinflaptothelymphnodewas

interrupted,orthedraininglymphnodewasdestroyedpriortotheinitialsensitiza-

tion,thetypicalsecondaryresponsewasnotobserved—leadingtotheconclusion

thatnoTcellresponsewasinduced.Followinganinitialsensitizationatanyother

locationontheskinthesecondaryresponsewasobserved,evenontheskin

flapregardlessofinterruptionofthelymphvesselordestructionofthedraining

lymphnode.Thisresultindicatedthattheantigen-experiencedeffectorlympho-

cytesreachedthesiteofantigenviathebloodstream.

ManyselfantigensareignoredbyCD8+cells.ATransgenicmouseencodingaviral

glycoproteingene.Asacomparisontothemanyself-antigenspresentintheperiph-

eralnon-lymphoidorgansandcells,ageneencodingaviralglycoprotein(GP)was

incorporatedintomice,underthecontrolofaregulatorygenewhichallowedGP

expressiononlywithinthepancreaticinsulin-producingbcells.Thisartificiallyin-

tegrated“selfantigen”wasignoredbythehost’simmunesystem,asindicatedby

theabsenceofbcelldestructionorautoimmunity(diabetes).WhentheGPexpres-

singtransgenicmousewasinfectedwithavirusencodingtheGPgene,whichin-

fectslymphoidorgans,GP-specificcytotoxicTcellswereinducedandthesecells

destroyedthetransgenicisletcells,resultingintheonsetofdiabetes.

Thismodeldemonstratedthatmanyself-antigensareignoredbytheimmunesys-

temsimplybecausetheyareonlypresentoutsideofthelymphaticsystem.How-

ever,shouldsuchantigensentertheimmunesysteminasuitableform(inthiscase

byviralinfection)thehostwillproduceanautoimmuneT-cellresponse.

92 2 BasicPrinciplesofImmunology

2

All rights reserved. Usage subject to terms and conditions of license

Kayser, Medical Microbiology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.