Biased signaling pathways via CXCR3 control the development and function of CD4+ T cell subsets

[摘要] Structurallyrelatedchemotacticcytokines(chemokines)regulatecelltraffickingthroughinteractionswith7‐transmembranedomain,Gprotein‐coupledreceptors.Biasedsignalingorfunctionalselectivityisaconceptthatdescribesasituationwherea7‐transmembranedomainreceptorpreferentiallyactivatesoneofseveralavailablecellularsignalingpathways.Itcanbedividedinto3distinctcases:ligandbias,receptorbias,andtissueorcellbias.Manystudies,includingthosecomingfromourlab,haveshownthatonlyalimitednumberofchemokinesarekeydriversofinflammation.Wehavereferredtothemas“driverchemokines.”TheyincludetheCXCR3ligandsCXCL9andCXCL10,theCCR2ligandCCL2,all3CCR5ligands,andtheCCR9ligandCCL25.AsforCXCR3,despitetheproinflammatorynatureofCXCL10andCXCL9,transgenicmicelackingCXCR3displayanaggravatedmanifestationofdifferentautoimmunedisease,includingTypeIdiabetesandexperimentalautoimmuneencephalomyelitis.Recently,weshowedthatwhereasCXCL9andCXCL10induceeffectorTh1/Th17cellstopromoteinflammation,CXCL11,witharelativelyhigherbindingaffinitytoCXCR3,drivesthedevelopmentoftheforkheadboxP3‐negativeIL‐10highTregulatory1cellsubsetandhence,dampensinflammation.WealsoshowedthatCXCL9/CXCL10activatesadifferentsignalingcascadethanCXCL11,despitebindingtothesamereceptor,CXCR3,whichresultsinthesediversebiologicactivities.Thisprovidesnewevidencefortheroleofbiasedsignalinginregulatingbiologicactivities,inwhichCXCL11inducesligandbiasatCXCR3andreceptor‐biasedsignalingviaatypicalchemokinereceptor3...

[学科分类] 生理学

[关键词] chemokines;CXCL12;regulatory T cells;tolerance;immunotherapy