Theadaptiveimmunesystemhasevolvedtorecognizeanddestroyavirtuallyinfinitevarietyofpathogenswhileremainingunresponsivetowardsself-tissues;thisstateisknownasimmunetolerance.Immunetoleranceismain-tainedbyamultilayered,interconnectedandredundantarrayofdominantandrecessivemechanisms,ensuringthatimmuneresponsesareregulatedinaneffectiveandtimelymanner1,2.Recessiveimmunetolerancemecha-nismsarecellintrinsicandincludethedeletionofself-reactiveimmunecells,renderingthemnon-functional(thatis,subjecttoanergy)andincreasingthenumberofinhibitoryreceptorsonimmunecellstoincreasetheiractivationthreshold.Bycontrast,dominantimmunetolerancemechanismsarecellextrinsicandarecarriedoutbysubsetsofspecializedimmunecellsthatactivelysuppresstheactivation,expansionandfunctionofotherimmunecells,therebyregulatingtheintensityandthedurationofimmuneresponses.Autoimmunedisordersarisefromdefectsinimmunetoleranceandaffectmorethan50millionindividualsintheUnitedStatesaloneandmorethan4%oftheworldpopulation.Progressintreatingindividualswiththesediseaseshasbeenslowowingtothecomplexmecha-nismsunderlyingthebalancebetweenimmunereac-tivityandimmunetolerance.Althoughsmall-moleculeandbiologictreatmentscanalleviatesymptoms,theyareoftennon-specific,requirelong-termadministration(andthuslong-termexposuretothetoxiceffectsassociatedwiththem)anddonotaccountforvari-abilityinunderlyingdiseasepathogenesisanddrugresponses.Forinstance,themainstaytreatmentforseveresystemiclupuserythematosus,anautoimmunedis-ordercausedbyautoreactiveBcells,issteroids,whichnon-specificallysuppressinflammation.Livingdrugs,suchasregulatoryTcells(Tregcells),mayhavegreaterspecificityandmorecomplextherapeuticbenefitsthanconventionalimmunosuppressivedrugs(suchasste-roidsandciclosporin),biologics(suchasrituximabandbelimumab),antimetabolites(suchasazathioprineandmethotrexate)andalkylatingagents(suchascyclo-phosphamide),amongstothers,andcouldpotentiallycurediseasebyrestoringimmunetolerance.Tcell-basedantigen-specificimmunetolerancewasfirstpostulatedin197...
