Medical Microbiology

formoftoleranceinvolvesantigenrecognitionbyantigen-reactiveperipheralT

cells,followedbyaprocessofclonalcellproliferation,enddifferentiation

anddeath.Thefollowingmechanismshavebeenpostulated,andinsome

casesconfirmed,toaccountforalackofperipheralT-cellresponsiveness

(Table2. 5 ,p. 7 1):

&T-cellindifferenceorignorance.Bothhostandforeignantigenspresent
onlywithinperipheralepithelial,mesenchymalorneuroectodermalcellsand
tissues—andwhichdonotmigrate,orarenottransportedbyAPCs,insuffi-
cientamountstotheorganizedlymphoidorgans—aresimplyignoredbyT
andBcells.Mostself-antigens,notpresentintheserumorinlymphohema-
topoieticcells,belongtothiscategoryandareignoreddespitethefactthat
theyarepotentiallyimmunogenic.Certainviruses,andtheirantigens,actu-
allytakeadvantageofthissystemofignorance.Forinstance,theimmune
systemignorestherabiesviruswhenitisrestrictedtoaxons,andpapilloma
virusesaslongastheantigensarerestrictedtokeratinocytes(warts).The
mainreasonwhymanyselfantigens,andsomeforeignantigens,areignored
byTcellsisthatimmuneresponsescanonlybeinducedwithinthespleenor
inlymphnodes,andnon-activated(ornaive)Tcellsdonotmigrateintothe
periphery.IthasalsobeenpostulatedthatthosenaiveTandBcellswhichdo
encounterantigensintheperipherywillbecomeanergized,orinactivated,
duetoalackoftheso-calledcostimulatoryorsecondarysignalsatthesesites.
However,theevidencesupportingthistheoryisstillindirect.Experiments
seekingtounderstandthe“indifference”ofTcellsaresummarizedinthe
boxonp.92f.Inallprobability,agreatmanyself-antigens(aswellasperiph-
eraltumors)areignoredbytheimmunesysteminthisway.Theseself-anti-
gensrepresentapotentialtargetforautoimmunity.

&Complete,exhaustiveT-cellinduction.Whenanantigen,selfornon-self,
entersalymphoidorganitencountersmanyAPCsandTcells,resultingin
theextremelyefficientactivationthoseTcellscarryingtheappropriate
TCR.DuringsuchascenariotherespondingTcellsdifferentiateintoshort-
livedeffectorcellswhichonlysurvivefortwotofourdays.Thisinduction
phasemayactuallycorrespondtothepostulatedphenomenonofanergy
(seeTable2. 5 ,p. 7 1).Shouldthisbethecase,anergy—definedastheinability
ofTcellstoreacttoantigenstimulationinvitro—mayinfactbeexplained
bytherespondingcellshavingalreadyenteredapathwayofcelldeath
(apoptosis)(seeFig.2. 17 ,p.88).Oncealltheterminallydifferentiatedeffector
Tcellshavedied,immunereactivityagainstthestimulatingantigenends.
Toleranceishereaftermaintained,asshouldtheresponsibleantigenhave
enteredintothethymusthosenewlymaturingthymocyteswillbesubjected
totheprocessofnegativeselection(e.g.,asseeninchronicsystemic(viremic)
infectionswithnoncytopathicviruses).Moreover,thosenewlymaturedT
cellswhichmayhaveescapednegativeselectionandemigratedintotheper-

ImmunologicalTolerance 91

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Kayser, Medical Microbiology © 2005 Thieme

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