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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: chemokines;    CXCL12;    regulatory T cells;    tolerance;    immunotherapy;   

DOI  :  10.1189/jlb.2MR0915-441R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 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...

【 授权许可】

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