Human T cell activation induces synaptic translocation and alters expression of the serine protease inhibitor neuroserpin and its target protease

摘要

ContactbetweenTcellsandAPCsandactivationofaneffectiveimmuneresponsetriggercellularpolarizationandtheformationofastructuredinterfaceknownastheimmunologicalsynapse.InteractionsacrossthesynapseandsecretionofTcellandAPC‐derivedfactorsintotheperisynapticcompartmentregulatesynapseformationandactivationofTcells.Wereportthattheserineproteaseinhibitorneuroserpin,anaxonallysecretedproteinthoughttoplayrolesintheformationoftheneuronalsynapseandrefinementofsynapticactivity,isexpressedinhumannai¨veeffectormemoryandcentralmemorysubsetsofCD4+andCD8+Tcells,aswellasmonocytes,Bcells,andNKcells.NeuroserpinpartiallycolocalizedwithaTGN38/LFA‐1‐positivevesiclepopulationinTcellsandtranslocatestotheimmunologicalsynapseuponactivationwithTCRantibodiesorantigen‐pulsedAPCs.ActivationofTcellstriggeredneuroserpinsecretion,arapid,8.4‐foldup‐regulationoftheserineproteasetissueplasminogenactivator,theproteasetargetforneuroserpin,andadelayed,6.25‐folddown‐regulationofneuroserpinexpression.Evidenceofpolarizationandregulatedneuroserpinexpressionwasalsoseeninexvivoanalysesofhumanlymphnodesandblood‐derivedTcells.IncreasedneuroserpinexpressionwasseeninclustersofTcellsintheparacortexofhumanlymphnodes,withsomeshowingpolarizationtoareasofcell:cellinteraction.Ourresultssupportaroleforneuroserpinandtissueplasminogenactivatorinactivation‐controlledproteolyticcleavageofproteinsinthesynapticorperisynapticspacetomodulateimmunecellfunction...