Medical Microbiology

&Blymphocytes—theseserveasatypeofAPCforThelpercellsduringT-B
collaborations.
TheconsequencesofMHCvariation.Becauseeveryindividualdifferswith
regardtothesetofpolymorphicMHCmoleculesandselfantigensexpressed
(withtheexceptionofmonozygotictwinsandinbredmiceofthesamestrain),
thedifferencesbetweentwogivenindividualsareconsiderable.Thehighde-
greeofvariabilityinMHCmolecules—essentialforthepresentationofalarge
proportionofpossibleantigenicpeptidesforT-cellrecognition—resultsin
thesemoleculesbecomingtargetsforTcellrecognitionfollowingcellular
ororgantransplantationresultingintransplantrejection.Theterm“trans-
plantationantigens”isthereforeamisnomer,andisonlyusedbecausetheir
realfunctionwasnotdiscovereduntilalatertime.Normallyantigensareonly
recognizedbyTcellsiftheyareassociatedwithMHC-encodedself-structures.
Transplantrecognition,whichapparentlyinvolvestheimitationofthecom-
binationofanon-selfantigenplusaself-MHCmolecule,canthereforebecon-
sideredanexception.TheprocessprobablyarisesfromT-cellreceptorcross-
reactivitybetweenhostself-MHCantigensplusforeignpeptidesontheone
hand,andnon-selftransplantationantigensassociatedwithself-peptides
fromthedonorontheotherhand(forexample,theT-cellreceptorfor
HLA-A2peptideXcross-reactswithHLA-A1 3 peptideY).Transplantrejection
isthereforeaconsequenceoftheenormousvarietyofcombinationsofanti-
genicpeptideplusMHC,whichisexhibitedbyeachindividualorganism.

T-CellMaturation:PositiveandNegativeSelection

MaturationofTcellsoccurslargelywithinthethymus.Fig.2. 2 (p. 4 7)showsa

schematicpresentationofthisprocess.BecausetheMHC-encodedpresenta-

tionmoleculesarehighlypolymorphic,andarealsosubjecttomutation,the

repertoireofTCRsisnotgeneticallypre-determined.Oneprerequisitefor

anoptimalrepertoireofT-cellsisthereforethepositiveselectionofTcells

suchthatthesepreferentiallyrecognizepeptidesassociatedonlywithself

transplantation(MHC)antigens.Asecondprerequisiteisnegativeselection,

whichinvolvesthedeletionofTcellsthatreacttoostronglyagainstselfMHC

plusselfpeptide.Therandomprocessesgoverningthegeneticgenerationof

anarrayofT-cellreceptorsresultsaborcdreceptorchaincombinations

whichareinthemajorityofcasesarenon-functional.ThoseTcellspreserved

throughtomaturityrepresentcellscarryingreceptorscapableofeffectively

recognizingself-MHCmolecules(positiveselection).However,theTcells

withinthisgroupwhichexpresstoohighanaffinityforself-MHCplus

self-peptidesaredeleted(negativeselection).

Theprocessofpositiveselectionwasdemonstratedinexperimentalmice

expressingMHCclassImoleculesoftypeb(MHCclassIb)fromwhichthe

TheT-CellSystem 63

2

Kayser, Medical Microbiology © 2005 Thieme