Duringanimmuneresponse,Bcellsthatencountertheircognateantigenbecomeactivatedanddifferen-tiatetoformshort-livedantibody-secretingcellsorgerminalcentre(GC)-independentmemoryBcells(MBCs).WithintheGC,BcellsengagewithantigenandcompeteforlimitingamountsofTcellhelp,whichisnecessaryforBcellsurvival,proliferationandeven-tualdifferentiationintoplasmacellsorGC-derivedMBCs1.TheGCisalsotheprimarysiteinwhichBcellsundergosomatichypermutation,withBcellsthataccrueproductivemutationspreferentiallyreceivingTcellhelp.TheGCresponseisrequiredforthedevelopmentofaffinity-maturedplasmacellsandMBCs(Box1).MBCsareanimportantcomponentofprotectiveimmunity.MBCsaredistinguishedbytheircapacitytosurvivelongtermandtorapidlydifferentiateintoantibody-secretingcellsuponantigenre-encounter.MBCscanalsore-entertheGCduringrecallresponses,wheretheyundergofurthersomatichypermutation2–5.MBCstendtoemergefromtheGCduringtheearlyphasesoftheGCresponseandtypicallydisplayreducedlevelsofsomatichypermutationandaffinitymaturationrelativetoplasmacells6–8.Inthecontextofviralinfec-tions,thereducedmutationalloadofMBCsallowsthesecellstomaintainenhancedflexibilityintheirrespon-sivenesstodifferentviralsubtypescomparedwithplasmacells,whichtendtobespecificforaparticularsubtype.Indeed,theMBCpopulationcontainsanele-vatedfractionofbroadlyreactiveclonesrelativetotheplasmacellpoolfornumerouspathogensinbothmiceandhumans9–12.TheMBCresponsecomprisesmultiplesubsets,identifiedbasedontheirexpressionofCD80andPDL2,amongothermarkers5,8(Box2).TheseMBCsubsetsemergefromtheGCatdifferenttimesandvaryintheircapacitytore-entertheGCordifferentiateintoantibody-secretingcellsuponantigenre-encounter5,6.Iterativeexposuretocross-reactiveviralantigensisanemergingvaccinationstrategydesignedtoelicitbroadlyreactiveMBCscapableofmediatingheterosubtypicimmunityagainstpathogenssuchasinfluenza.Thepoten-tialefficacyofaniterativevaccinationstrategyislimitedbytherelativeinefficiencywithwhichmostMBCclonesre-entertheGCresponse13–15.ThesecondaryGCresponsetendstoco...
