Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

[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...

[学科分类] 生理学

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