CD152 (CTLA-4) Determines CD4 T Cell Migration In Vitro and In Vivo 英文参考文献.docVIP

CD152(CTLA-4)DeterminesCD4TCellMigrationInVitro andInVivo KarinKnieke1,2,HolgerHoff2,FrankMaszyna2,PaulaKolar2,ArnhildSchrage2,AlfHamann2,GudrunF. Debes3,MonikaC.Brunner-Weinzierl1,2* 1Experimentelle Pa¨diatrie, Universita¨tskinderklinik – Otto-von-Guericke Germany, 2Deutsches Rheuma-Forschungszentrum Berlin and Universita¨t, Magdeburg, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinischer Immunologie, CCM, Charite′ -Universita¨tsmedizin Berlin, Berlin, Germany, 3Department of Pathobiology,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica Abstract Background:Migrationofantigen-experiencedTcellstosecondarylymphoidorgansandthesiteofantigenic-challengeisa mandatoryprerequisitefortheprecisefunctioningofadaptiveimmuneresponses.ThesurfacemoleculeCD152(CTLA-4)is mostlyconsideredasanegativeregulatorofTcellactivationduringimmuneresponses.Itiscurrentlyunknownwhether CD152canalsoinfluencechemokine-drivenTcellmigration. Methodology/PrincipalFindings:WeanalyzedtheconsequencesofCD152signalingonThcellmigrationusingchemotaxis assaysinvitroandradioactivecelltrackinginvivo.WeshowherethatthegeneticandserologicalinactivationofCD152in Th1 cells reduced migration towards CCL4, CXCL12 and CCL19, but not CXCL9, in a G-protein dependent manner. In addition, retroviral transduction of CD152 cDNA into CD152 negative cells restored Th1 cell migration. Crosslinking of CD152togetherwithCD3andCD28stimulationonactivatedTh1cellsincreasedexpressionofthechemokinereceptors CCR5 and CCR7, which in turn enhanced cell migration. Using sensitive liposome technology, we show that mature dendritic cells but not activated B cells were potent at inducing surface CD152 expression and the CD152-mediated migration-enhancingsignals.Importantly,migrationofCD152positiveTh1lymphocytesininvivoexperimentsincreased morethan200%ascomparedtoCD152negativecounterpartsshowingthatindeedCD152orchestratesspecificmigration ofselectedTh1cellstositesofinflammationandantigeni