Medical Microbiology

immunologicalrejectionofcelltransfusionsortissueandorgantransplants.

Itstruefunctionasapeptide-presentingmoleculewasnotdiscovereduntil

theseventies,whenitsrolebecameapparentwhilsttestingthespecificityof

virus-specificcytotoxicTcells.Duringtheseexperimentsitwasobservedthat

immuneTcellswereonlyabletodestroyinfectedtargetcellsifbothcelltypes

werederivedfromthesamepatientorfrommicewithidenticalMHCmol-

ecules.TheresultingconclusionwasthataT-cellreceptornotonlyrecognizes

thecorrespondingaminoacidstructureofthepresentedpeptide,butaddi-

tionallyrecognizescertainpartsoftheMHCstructure.Itisnowknownthat

thiscontactbetweenMHContheAPCandtheT-cellreceptorisstabilizedby

theco-receptorsCD4andCD8.

MHCclasses.MoleculesencodedbytheMHCcanbeclassifiedintothree

groupsaccordingtotheirdistributiononsomaticcells,andthetypesofcells

bywhichtheyarerecognized:

&MHCclassImolecules.Thesemoleculesconsistofaheavyachainwith
threeIg-likepolymorphicdomains(theseareencodedby 100 – 1000 alleles,
withthea 1 anda 2 domainsbeingmuchmorepolymorphicthanthea 3 do-
main)andanonmembrane-bound(soluble)single-domainb 2 microglobulin
(b 2 M,whichisencodedbyarelativelysmallnumberofalleles).Theachain
formsagroovethatfunctionstopresentantigenicpeptides(Fig.2. 7 ).Human
HLA-A,HLA-B,andHLA-Cmoleculesareexpressedinvaryingdensitiesonall
somaticcells(therelativeHLAdensitiesforfibroblastsandhepaticcells,lym-
phocytes,orneuronsare1x, 10 0xand0. 1 !,respectively).Additional,non-
classical,classIantigenswhichexhibitalowdegreeofpolymorphismare
alsopresentonlymphohematopoieticcellsandplayaroleincellulardiffer-
entiation.

&MHCclassIImolecules.Thesearemadeupbytwodifferentpolymorphic
transmembranechainsthatconsistoftwodomainseach(a 1 ishighlypoly-
morphic,whilstb 1 ismoderatelypolymorphic,andb 2 isfairlyconstant).
Thesechainscombinetoformtheantigen-presentinggroove.ClassIImole-
culesarelargelyrestrictedtolymphohematopoeticcells,antigen-presenting
cells(APC),macrophages,andsoon.(seeFig.2.9a,p.65)Inhumans,but
notinmice,theyarealsofoundonsomeepithelialcells,neuroendocrinecells,
andTcells.TheproductsofthethreehumangeneregionsHLA-DP,HLA-DQ
andHLA-DRcanadditionallyformmoleculesrepresentingcombinationsof
twoloci—thusprovidingadditionaldiversityforpeptidepresentation.

&MHCclassIIImolecules.ThesemoleculesarenotMHCantigensinthe
classicalsense,butareencodedwithintheMHClocus.Theseincludecom-
plement(C)componentsC4andC2,cytokines(IL,TNF),heatshockprotein 70
(hsp70),andotherproductsimportantforpeptidepresentation.

TheT-CellSystem 59

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Kayser, Medical Microbiology © 2005 Thieme