Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1‐associated periodic syndrome

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

关键词: TRAPS;    Tregs;    Tconvs;    autoimmunity;    immune tolerance;   

DOI  :  10.1189/jlb.3A0915-399R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

TNFR‐associatedperiodicsyndromeisanautoinflammatorydisordercausedbyautosomal‐dominantmutationsinTNFRSF1A,thegeneencodingforTNFRsuperfamily1A.ThelackofknowledgeinthefieldofTNFR‐associatedperiodicsyndromebiologyisclear,particularlyinthecontextofcontrolofimmuneself‐tolerance.WeinvestigatedhowTNF‐α/TNFRsuperfamily1AsignalingcanaffectTcellbiology,focusingonconventionalCD4+CD25−andregulatoryCD4+CD25+TcellfunctionsinpatientswithTNFR‐associatedperiodicsyndromecarryingeitherhighorlowpenetranceTNFRSF1Amutations.Specifically,weobservedthatinhighpenetranceTNFR‐associatedperiodicsyndrome,atthemolecularlevel,thesealterationsweresecondarytoahyperactivationoftheERK1/2,STAT1/3/5,mammaliantargetofrapamycin,andNF‐κBpathwaysinconventionalTcells.Inaddition,thesepatientshadalowerfrequencyofperipheralregulatoryTcells,whichalsodisplayedadefectivesuppressivephenotype.ThesealterationswerepartiallyfoundinlowpenetranceTNFR‐associatedperiodicsyndrome,suggestingaspecificlinkbetweenthepenetranceoftheTNFRSF1AmutationandtheobservedTcellphenotype.Takentogether,ourdataenvisionanovelroleforadaptiveimmunityinthepathogenesisofTNFR‐associatedperiodicsyndromeinvolvingbothCD4+conventionalTcellsandTregs,suggestinganovelmechanismofinflammationinthecontextofautoinflammatorydisorders...

【 授权许可】

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