TheactivationofTcellsrequiresaco-stimulatorysignalwithTcellreceptoractivation,providedinmanycasesbyactivationofCD28inrestingTcells.4-1BB(CD137)isamemberoftheTNFreceptorgenefamilythatprovidesanotherTcellco-stimulatorysignal.4-1BBisexpressedbyactivatedcytotoxicandhelperTcellsanditsexpressionisinducedbyavarietyofTcellstimuli,includingactivationoftheTcellreceptororstimulationwithmitogens.Theligandfor4-1BB(4-1BBL)isinducedonactivatedantigen-presentingcellsincludingmacrophages,activatingTcellsexpressing4-1BB.Micelacking4-1BBsurviveandhaveanalteredthoughfunctionalimmuneresponse.Tcellsofmicelacking4-1BBproliferatemorerapidlythannormalTcells,buthavereducedcytokinesecretion.Thecostimulatorysignalprovidedby4-1BBmayactincombinationwithCD28activationtoprolongtheTcellresponse,andmayalsoactindependentlyofCD28.StimulationofTcellswiththe4-1BBligandmayprovideatherapeuticimmuneresponseinthetreatmentofcancerorviralinfection.4-1BBinTcellsactivatesseveralsignalingpathways.LikeothermembersoftheTNFreceptorfamily,the4-1BBreceptordoesnothaveanintrinsickinaseactivity.TRAF2isasignalingadapterthatmediatessignalingbyothermembersoftheTNFreceptorfamilyandthatalsobindstothecytoplasmicdomainofligandactivated4-1BBtoactivateintracellularkinasecascades.TRAF1alsobindstothecytoplasmicdomainof4-1BBalthoughwithloweraffinitythanTRAF2.Onedownstreameffectoractivatedby4-1BBthroughTRAF2isthetranscriptionfactorNF-kB.4-1BBalsoactivatesmapkinasepathways,includingp38andJNKactivation.ASK1dependentpathwayscanactivatebothp38andJNK,anddominantnegativeASK1blockstheiractivation.Otherkinasepathwaysmayalsobeinvolvedin4-1BBactivationofp38andJNK,suchasactivationofgerminalcenterkinase(GCK)orrelatedkinasesinvolvedinactivationofJNKandp38byTNF.MapkinaseactivationalongwithNF-kBactivationresultsintranscriptionalactivationofcytokinegenesinvolvedinTcellactivationandsignaling.Theco-stimulatorysignalingprovidedby4-1BBsharessomefeatureswithCD28signaling,providinganexplanationfortheABIlityof4-1BBtoreplacetheCD28costimulatorysignalinsomesettings.

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