Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

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

关键词: molecules;    T cells;    B‐;    1 cells;    autoimmunity;    cell activation;    transgenic/knockout mice;   

DOI  :  10.1189/jlb.0312152

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Lymphocyteactivationiscrucialforthegenerationofimmuneresponses.InvitrostudieshavedemonstratedthatTRAPsarecriticalregulatorsoflymphocyteactivation.However,morerecentinvivostudieshavedemonstratedthatwiththeexceptionofLAT,TRAPs,suchasSIT,NTAL,andLAX,onlyminimallyaffectimmunecellfunctions.AdditionalstudieshavesuggestedthatthemildortheapparentlackofaphenotypedisplayedbymostTRAPKOmicemaybeexplainedbyfunctionalredundancyamongthisfamilyofadaptors.Infact,ithasbeenshownthatthephenotypeofNTAL/LATorSIT/TRIMdouble‐deficientmiceismoreseverethanthatofthesingleKOs.Here,wehaveevaluatedwhetherSITandtherelatedtransmembraneadaptorLAXhaveoverlappingfunctionsbygeneratingSIT/LAXDKOmice.WeshowthatDKO,incontrasttosingleKOmice,accumulatelargenumbersofactivatedCD4+Tcellsinthespleen.Moreover,conventionalBcellsfromDKOmicearehyperproliferativeuponCD40stimulation.Additionally,wefoundthatDKOmicedisplayedanexpansionoftheB1cellpoolintheperitonealcavity,hypergammaglobulinaemia,andanenhancedimmuneresponsetotheT1‐independentantigen,TNP‐LPS.Finally,wedemonstratethatSIT/LAXdoubledeficiencyresultedinamorepronouncedbreakdownofperipheraltoleranceandthedevelopmentofautoimmunitycharacterizedbyANAsandrenaldisease(glomerulonephritisandproteinuria).Collectively,ourdataindicatethatSITandLAXareimportantnegativeregulatorsofimmuneresponsesthatfunctionallycooperate...

【 授权许可】

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